Factor V Leiden (FVL) is the most common inherited disorder that increases the tendency of blood to clot, a condition known as thrombophilia. This genetic change affects the Factor V protein, a component of the body’s clotting system. When the mutation is present, it makes the blood more prone to forming clots, particularly in the deep veins. This article focuses on the risks associated with the heterozygous form of Factor V Leiden, which is the most frequently encountered type.
Understanding the Heterozygous Mutation
The Factor V protein is coded by the F5 gene and plays a part in the coagulation cascade, helping to generate the final clot material. Factor V Leiden is caused by a single-point mutation in the F5 gene, which instructs the body to produce an altered Factor V protein.
A heterozygous person inherits one mutated F5 gene copy and one normal copy. This autosomal dominant pattern results in the carrier having a mix of both normal and abnormal Factor V Leiden protein circulating in their blood.
The heterozygous form is far more common than the homozygous form, where two copies of the mutated gene are inherited. While the homozygous form confers a much higher risk, the heterozygous form is associated with a lower, still elevated, risk.
How Factor V Leiden Increases Clotting Risk
The clotting process is regulated by a natural anticoagulant system that limits clot formation once it has started. A primary regulator is Activated Protein C (APC), an enzyme that inactivates the Factor V protein. This inactivation process stops the excessive production of thrombin, the enzyme responsible for creating the final fibrin clot.
The Factor V Leiden mutation changes the Factor V protein’s structure at a specific cleavage site, making it resistant to inactivation by APC. Because the APC enzyme cannot easily degrade the mutated Factor V protein, the normal “off switch” is compromised.
This resistance means the Factor V Leiden protein remains active in the blood for a longer duration than normal. This prolonged activity leads to an extended generation of thrombin, creating a state of hypercoagulability. Consequently, the clotting process takes significantly longer to shut down, increasing the chance of inappropriate clotting.
Clinical Implications and Specific Risk Factors
The primary clinical concern for heterozygous Factor V Leiden carriers is the increased risk of venous thromboembolism (VTE). VTE includes deep vein thrombosis (DVT), typically a clot in a deep vein of the legs, and pulmonary embolism (PE). A PE occurs if a portion of the clot breaks off and travels to the lungs, which can be life-threatening.
For individuals with the heterozygous mutation, the relative risk of developing a first DVT is increased by approximately three- to eightfold compared to the general population. Despite this relative risk, the absolute lifetime risk of experiencing a clot remains low, estimated to be 10% or less for most carriers.
Certain life events and medical circumstances act as powerful triggers that interact with the underlying genetic predisposition. A significant risk multiplier is the use of estrogen-containing medications, such as combined oral contraceptives or hormone replacement therapy. For women with the heterozygous mutation, combining this genetic factor with estrogen use can increase the risk of VTE up to 30-fold compared to non-carriers.
Other major circumstantial risk factors involve periods of reduced blood flow or vessel injury. These include major surgery, especially orthopedic procedures, and prolonged immobility, such as long-distance travel or hospital bed rest. Pregnancy and the postpartum period also elevate the risk, with women who are heterozygous for FVL facing a five- to eightfold greater risk of pregnancy-related VTE than non-carriers.
Testing and Long-Term Management Strategies
Diagnosis of Factor V Leiden often begins with the Activated Protein C Resistance (APCR) assay, a functional blood test. This is typically used if a person has experienced an unexplained clot or has a strong family history. The APCR assay measures how well the patient’s plasma responds to APC; a low ratio suggests resistance, which is then confirmed by a definitive DNA-based genetic test to identify the specific mutation in the F5 gene.
For asymptomatic heterozygous individuals who have never experienced a clot, the standard management approach is preventive surveillance rather than routine long-term use of anticoagulant medication. Management focuses on avoiding known high-risk triggers. Women are advised to avoid estrogen-containing contraceptives and hormone replacement therapy due to the substantial increase in clotting risk.
During high-risk periods, such as before and after major surgery or during long periods of immobility, a short course of prophylactic anticoagulation may be recommended. Lifestyle modifications, such as maintaining hydration and ensuring regular movement during travel, are important preventive measures.
If a heterozygous carrier has experienced a VTE, the initial treatment involves anticoagulant medications, often for at least three months. The decision to continue anticoagulation indefinitely is based on a comprehensive risk assessment. The heterozygous FVL mutation alone does not typically warrant lifelong blood thinners for a single provoked clot. The assessment weighs the risk of recurrent clotting against the bleeding risk associated with long-term anticoagulation.