Clinical Articles

Testing for Factor V Leiden and prothrombin G20210A mutations

By Dawn L Thiselton, PhD, Senior Writer/Editor, HDL, Inc.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are manifestations of a single disease entity, venous thromboembolism (VTE). Each year in the US > 400,000 people develop a VTE; 200,000 of these are complicated by a PE (50% of which are fatal). However, in recent years, our understanding of the mechanisms underlying hypercoagulable states has improved, resulting in an array of risk factors known to influence VTE occurrence. These risk factors range from the well-known environmental factors such as smoking and oral contraceptive use to genetically inherited risks such as the Factor V Leiden or prothrombin gene mutation.

Factor V Leiden (FVL) is a genetic variant of protein factor V, a cofactor involved in the blood clotting process. Activated protein C (APC) is a natural anticoagulant that limits clotting by degrading factor V. The FVL mutation makes factor V less responsive to APC inactivation, rendering FVL carriers susceptible to VTE and potentially clot migration, leading to myocardial infarction, stroke or PE1. A single FVL allele occurs in ~5% Caucasians, 2.2% Hispanics and 1.2% African-Americans in the US, making FVL the most frequent inherited risk factor for VTE (3-8 fold increased risk)2.

The prothrombin (Factor II) G20210A mutation is the second most common inherited risk factor for VTE and results from an alteration in the 3’-untranslated region of the prothrombin gene (the precursor to thrombin)3. The heterozygote carrier frequency is 2.2% in Caucasians, 2.2% in Hispanics and 0.6% in African-Americans in the US. The prothrombin mutation confers 3-8 fold increased risk for VTE, via increased circulating prothrombin levels which enhance potential for clot formation3.

Compound heterozygotes for both FVL and the prothrombin mutation have a ~20-80 fold increased risk of VTE, similar to individuals homozygous for either mutation, but occurring at a younger age. In a recent study of >22,000 first episode VTE patients, those with FVL or prothrombin G20210A developed their first VTE 10 years earlier than those who tested negative. However, this difference was mostly due to the high proportion of women using oral contraceptives or who were pregnant4. Thus, in addition to the increased risk for primary VTE and possibly recurrent VTE imposed by FVL and prothrombin G20210A, other factors impact the importance of these mutations in any individual; oral contraceptives, hormone replacement therapy (HRT), pregnancy, smoking, immobility, obesity, dehydration, surgery, hyperhomocysteinemia, diabetes, varicose veins, cancer and other anticoagulation deficits (e.g. MTHFR mutations, increased fibrinogen levels).

The FVL mutation test is recommended for a patient who has a personal or family history of recurrent VTE, has a first VTE while taking oral contraceptives/HRT, or during pregnancy. The treatment of a patient with FVL or prothrombin G20210A mutations depends upon the patient’s risk of recurrent VTE. Those with no previous history should take steps to prevent a VTE; avoid prolonged sitting or immobilization, exercise regularly (especially walking), maintain hydration, lose weight, stop smoking and consider alternative birth control to oral contraceptives. Surgery is a main cause of DVT (through increased clotting), so it is important that mutation carriers inform surgeons of their need for anticoagulation therapy in advance. For mutation carriers who have experienced a VTE, anticoagulation is typically initiated with heparin or oral warfarin and continued for 3-6 months after the VTE. Prolonged anticoagulation therapy is usually not indicated in FVL/prothrombin mutation carriers after a single VTE because of a risk of bleeding. Patients who have had VTEs or at high risk of additional episodes (homozygotes or compound heterozygotes) are candidates for long-term anticoagulation therapy.

Traditional guidelines have not recommended genetic screening as they were written when costs were prohibitive (>$2000/test). The FVL and prothrombin G20210A mutations now cost <$100. Given the commonplace nature of the environmental risk factors for VTE and the fact that simple lifestyle modifications can reduce risk, the utility of testing for these genetic variants extends to everybody.

  1. Bertina RM et al (1994) Nature 369(6475):64-7.
  2. Kujovich J. (Updated March 2010) Factor V Leiden thrombophilia. In: GeneReviews at GeneTests: Copyright, University of Washington, Seattle. Available at www.genetests.org.
  3. Kujovich J (Updated March 2010) Prothrombin-related thrombophilia. In: GeneReviews at GeneTests: Copyright, University of Washington, Seattle. Available at http://www.genetests.org.
  4. Gadelha T et al (2010) Thromb Res 126: 283.