In 1993, Dahlback and colleagues reported that a poor anticoagulant response to activated protein C was associated with the risk of thrombosis1. Subsequently, it appeared clear that the so-called activated protein C resistance is mostly caused by a mutation in the Arg506 cleavage site of activated factor V2–6. As a consequence, the activated mutant factor V molecule, commonly called factor V Leiden (FVL), is resistant to proteolytic inactivation by activated protein C and retains its procoagulant activity2. FVL mutation is inherited as an autosomal dominant trait and it is the most prevalent venous thrombotic risk factor in the Caucasian population, being present in 3–7% of individuals, but is rare in Asians and Africans7–10. Other less common inherited coagulation abnormalities include deficiencies of protein S and protein C, prothrombin G20210A mutation, and elevated levels of clotting factor VIII11.
Heterozygous carriers of FVL have an approximately 3- to 5-fold increased risk of venous thromboembolism (VTE), whereas the risk in homozygous carriers is estimated to be increased 80 times3. The absolute incidence of VTE in patients with FVL mutation ranges from 0.19% per year to 0.45% per year, compared to 0.10% per year in individuals without the mutation11. Vice versa, FVL is present in the heterozygous form in approximately 15–20% of VTE patients9. However, not all mutation carriers develop VTE and their absolute thrombotic risk will depend on the interaction between the FVL and other inherited thrombophilic mutations or acquired high-risk situations, such as age, pregnancy, immobilisation, prolonged travel, major or orthopaedic surgery, cancer, use of oral contraceptives and hormone replacement therapy3. For instance, the risk of VTE in a young woman with FVL with no family history of VTE is low, approximately 6/10,000 per year, but if this woman takes oral contraceptives, her risk increases 5-fold. Similar estimates can be made for FVL carriers who take hormone replacement therapy or who are pregnant12. In addition, FVL increases the risk of recurrent foetal loss, possibly due to placental thrombosis, and has also been associated with increased risk of severe pre-eclampsia, placental abruption, unexplained intrauterine foetal growth retardation, and stillbirth13–16.
The risk of recurrent VTE in carriers of FVL is less clear, as a number of prospective cohort studies have addressed this question, but with conflicting results17,18. However, a meta-analysis of ten pooled studies found that heterozygosity for FVL was associated with a 1.4-fold increased risk of recurrent VTE compared with the risk in people without this mutation19.
Thus, according to the American College of Medical Genetics20, testing for FV Leiden should be performed in the following circumstances: first VTE before 50 years of age, first VTE over 50 years of age in the absence of malignancy, venous thrombosis in unusual sites (such as hepatic, mesenteric and cerebral veins), recurrent VTE, first VTE and a strong family history of VTE, VTE during pregnancy, in the post-partum period or in women taking oral contraceptives or under hormone replacement therapy, women with unexplained pregnancy loss and asymptomatic adult family members of relatives with documented FVL. Indeed, identifying FV Leiden in the latter cases is very helpful as such individuals may benefit from targeted thromboprophylaxis in high-risk situations (e.g., pregnancy, puerperium, surgery, immobilisation and trauma), and the avoidance of acquired risk factors, most notably oral contraceptives. By contrast, FVL is not recommended as a general screening test, as a routine initial test during pregnancy, before use of oral contraceptives or hormone replacement therapy, or as a routine initial test in patients with arterial thrombosis21. In addition, given that FVL-associated thrombophilia is an adult-onset disorder with low penetrance, foetal testing and routine screening of neonates are not indicated.
Finally, another interesting field of potential application of FVL testing is the selection of blood donors22. A number of studies analysed the prevalence of this mutation in blood donors and found a distribution similar to that in the general population23,24, although in some cases a high prevalence of FVL carriers was detected25. However, considering the epidemiology of FVL in blood donors, the knowledge of their FVL status could be useful as it might influence their suitability for blood donation. Indeed, heterozygous FVL subjects are allowed to donate whole blood or by apheresis without any restriction, unless they are currently symptomatic or under antithrombotic therapy. Vice versa, individuals homozygous for FVL or with double heterozygosity for FVL and another inherited thrombophilic risk factor and a positive history of VTE should not donate whole blood or apheresis, while those with no history of VTE are allowed to donate whole blood (with elimination of the plasma component) but not by apheresis26. This practice is also aimed to safeguard the health of the blood donors as there are a few case reports describing thrombotic complications in donors with associated thrombophilia following apheresis donation, due to activation of the coagulation system caused by contact between the blood and artificial surfaces27,28. Table I summarises the utility of FVL testing.
In conclusion, the discovery of FVL has represented a great advance in the understanding of the molecular mechanisms leading to VTE. However, diagnostic thrombophilic work-up, including FVL testing, should be tailored on individual patient’s characteristics. Thus, when used appropriately, FVL testing can have a positive impact on the health care of the people tested and their family members.