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Molecular Testing for Factor V Leiden and Prothrombin Gene Mutations in Inherited Thrombophilia
Factor V Leiden
Factor V Leiden (FVL) refers to the specific G-to-A transition at nucleotide 1601 (c.1601G>A) in exon 10 of the factor V gene, which results in arginine to glutamine substitution at amino acid 534 of the protein (p.Arg534Gln), previously known as p.Arg506Gln. Activated factor V serves as a cofactor for the conversion of prothrombin to the active enzyme thrombin. Activated protein C (APC) is a natural anticoagulant, which cleaves and inactivates activated factor V. The FVL mutation abolishes one of the three APC cleavage sites, leading to APC resistance and increased thrombin generation. FVL thrombophilia is suspected in individuals with a history of venous thromboembolism (VTE) manifesting as deep vein thrombosis or pulmonary embolism, especially in women with a history of VTE during pregnancy or in association with oral contraceptive use and in individuals with a personal or family history of recurrent thrombosis.
FVL is the most common genetic cause of hereditary thrombophilia. In the United States, 3%–7% of the Caucasian population is heterozygous for this mutation. The prevalence is lower in other populations. Homozygous FVL mutations are found in about 1 in 5000 Caucasians. The FVL mutation is identified in ∼20% with first VTE episode and in 50%–60% of patients with recurrent VTE. In addition to FVL, other rare variants have been observed, including factor V Cambridge (p.Arg306Thr), factor V Liverpool (p.Ile359Thr), and p.Glu666Asp, which have been associated with thrombosis risk. Other rare polymorphisms, including c.1692A>C and c.1696A>G, are silent, and their clinical significance is unknown.
Prothrombin Gene Mutation
Prothrombin (factor II) is a vitamin K–dependent coagulation factor. On activation, prothrombin is proteolytically cleaved to form thrombin, and in turn acts as a serine protease that converts fibrinogen to fibrin. In addition, thrombin catalyzes many other coagulation-related reactions. Hyperthrombinemia has been mainly associated with a c.∗97G>A mutation (also known as G20210A) located in the 3′ untranslated region of the prothrombin gene. This mutation results in increased production through increased prothrombin mRNA expression and stabilization. High levels of prothrombin can lead to increased thrombin generation in the plasma, coagulation activation, and thrombosis. High prothrombin levels also inhibit APC-mediated inactivation of activated factor V and factor VIII.
Prothrombin mutations are the second most common inherited thrombophilia. In the United States, the heterozygous carrier frequency is about 1%–2%, accounting for approximately 6%–18% of VTE cases. This mutation is also more common in the Caucasian population and is rare in other ethnic groups. Homozygosity for this mutation is found in about 1 in 10,000 individuals. Transheterozygosity for FVL and prothrombin c.∗97G>A affects about 1 in 1000 individuals. Additional variations identified in the 3′-untranslated region of the prothrombin gene include changes at positions 20207, 20209, 20218, and 20221. The clinical significance of these polymorphisms is unclear.
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