Factor V Leiden (FVL) is a point mutation of factor V resulting in an elimination of cleavage site in factor V and factor Va. This genetic defect leads to an increased risk of thrombosis especially in homozygous or pseudo-homozygous FVL mutations. Many individuals with the mutation will never develop a venous thrombotic event (VTE). The decision about VTE risk reduction (both primary and secondary and prevention of recurrence) requires a great deal of clinical acumen, given that most of the people who carry the mutation will never have VTE.
Normally, factor V synthesis principally occurs in the liver. Thrombin activates factor V and once activated, it will convert prothrombin to thrombin.
Activated protein C, one of the principal physiologic inhibitor of coagulation degrades factor V. In the presence of what is called thrombomodulin; thrombin acts to decrease clotting by activating protein C; therefore, the concentration and the action of protein C are important determinants in the negative feedback loop through which thrombin limits its activation.
Factor V Leiden is an autosomal dominant genetic condition which exhibits incomplete penetrance, meaning that not every person who has the mutation will develop the disease.
FVL, also known as factor VR506Q and factor V Arg506 Gln, results from a single-point mutation in the factor V gene (guanine to adenine at nucleotide 1691), which leads to a single amino acid change (replacement of arginine with glutamine at amino acid 506). This abolishes the Arg506 cleavage site for aPC in Factor V and Va.
Heterozygosity for the FVL mutation is the most common inherited thrombophilia in the unselected Caucasian population (prevalence, approximately 1% to 5%) and is considered the most common inherited thrombophilia in individuals with venous thromboembolism (prevalence approximately 10% to 20%).  Heterozygosity of this gene increases the lifetime risk of thrombosis 7-fold, while homozygosity (which is rare) increases the risk 20- to 80-fold.
Despite the increase in the risk of VTE, there is no clinical evidence that heterozygosity to FVL increases the overall mortality.
Factor V Leiden (FVL) results from a single-point mutation in the factor V gene (guanine to adenine at nucleotide 1691) that would lead to the replacement of arginine with glutamine at amino acid 506. This abolishes the Arg506 cleavage site at aPC in factor V and factor Va. The consequences are enhancing the procoagulant role of factor Va and the reduced anticoagulant role of factor V.
The main clinical manifestation of the FVL (heterozygous) mutation is a risk for venous thromboembolism (VTE). However, the most common finding in individuals with FVL is a laboratory-only abnormality. Only a small percentage of individuals with FVL will develop VTE in their lifetime, with an approximate risk of 5% for FVL heterozygotes in the general population and up to 20% in thrombophilic families.
Testing for FVL is indicated for individuals with venous thromboembolism, especially if VTE occurs at a young age and if the VTE occurs in an unusual location such as a portal vein or cerebral vein. It is also indicated in a member of a thrombophilic family.
Testing usually is not performed in individuals with a first episode especially if it is provoked or if it occurs in people who are older than 50 years of age.
FVL can be diagnosed by mutation analysis (DNA testing) or a functional coagulation test for aPC resistance.
Management of venous thromboembolism in people with FVL mutation is the same as that of the general population, and FVL mutation will not affect the decision about which anticoagulant one should use. The choice of anticoagulant is based on some factors like patient preference, adherence to therapy, the severity of thrombosis and drug interactions.
Generally, direct oral anticoagulant (DOAC) are usually used for patients with typical VTE presentation. Warfarin is preferred if there is a concern about adherence or those who present with a submissive/massive pulmonary embolism who would benefit from maintaining INR at the high end of the therapeutic range.
The duration of VTE treatment is not different between FVL and the general population, and it depends on the risk of recurrent VTE. It is highly recommended that one continue indefinite anticoagulation for unprovoked, life-threatening venous thromboembolism, VTE at an unusual location or if it is recurrent.
Individuals with FVL heterozygous mutation who undergo surgery should be treated as a high-risk group and receive prophylactic anticoagulation.
The differential diagnosis for deep vein thrombosis (DVT) includes the following:
A proportion of the population with Factor V Leiden will suffer venous thrombosis. Thromboembolism, including pulmonary embolism, carries significant morbidity and mortality.
However, despite the increase in the risk of VTE, there is no evidence that heterozygosity to FVL increases overall mortality.
Factor V Leiden deficiency is not a common disorder, but because there is a potential risk of developing VTE, healthcare workers should be aware of this disorder. Patients may present with either venous or arterial thrombotic events, both of which are associated with a high morbidity and mortality. The condition is best managed by a multidisciplinary team that includes a hematologist, internist, nurse practitioner, a pharmacist, and the primary care provider. The key reason for such a team is that even when a diagnosis is made, many patients with only a laboratory finding of the defect may not require therapy. Only patients with VTE require treatment. The other difficulty in managing these patients is the duration of therapy. At the moment, data indicate that VTE in factor Leiden deficiency should be managed in the same manner as the normal population, but those with recurrent VTE or thrombosis of vessels in unusual locations may require long-term therapy. The outcomes in most patients with factor V Leiden deficiency are good but the outcomes in pregnant families with the disorder are guarded, because the risk of anticoagulation can adversely affect the fetus.