Factor V Leiden

Factor V Leiden (FVL) thrombophilia, also known as rs6025 or F5 p.R506Q, is a genetic mutation of human factor V, a protein integral to blood clotting. This mutation results in hypercoagulability, meaning an increased tendency for abnormal blood clot formation. The name Factor V Leiden originates from the Dutch city of Leiden, where it was first identified in 1994. It is the most common hereditary hypercoagulability disorder among ethnic Europeans and is inherited in an autosomal dominant manner with incomplete penetrance.

Signs and Symptoms

The presentation of Factor V Leiden varies significantly among individuals. While some never experience thrombosis, others may have recurrent thrombotic events before the age of 30. This variability is influenced by the number of F5 gene mutations, the presence of other genetic alterations related to blood clotting, and circumstantial risk factors such as surgery, pregnancy, and use of oral contraceptives.

Symptoms include:

• First deep vein thrombosis (DVT) or pulmonary embolism (PE) before age 50
• Recurring DVT or PE
• Venous thrombosis in unusual sites such as the brain or liver
• DVT or PE during or immediately after pregnancy
• History of unexplained pregnancy loss in the second or third trimester
• DVT or PE coupled with a strong family history of venous thromboembolism

The use of hormones, such as oral contraceptive pills (OCPs) and hormone replacement therapy (HRT), significantly increases the risk of developing DVT and PE, especially in women with Factor V Leiden.

Pathophysiology

In normal coagulation, factor V acts as a cofactor for factor Xa to activate prothrombin, resulting in thrombin formation, which ultimately leads to a fibrin clot. Activated protein C (APC) acts as a natural anticoagulant by degrading factor V. However, the Factor V Leiden mutation results in a factor V variant that is resistant to degradation by APC, leading to excessive thrombin generation and increased fibrin formation.

The mutation involves a single nucleotide polymorphism (SNP) in exon 10 of the F5 gene, causing a missense substitution from arginine to glutamine at position 506 or 534, depending on the numbering system. This alteration prevents the efficient inactivation of factor V by APC, promoting excessive clotting, primarily in veins, potentially leading to DVT and PE.

Diagnosis

Suspicion of Factor V Leiden should arise in any Caucasian patient under 45 or anyone with a family history of venous thrombosis. Diagnostic methods include:

• Clotting time tests using snake venom or activated partial thromboplastin time (aPTT), where a decreased clotting time in the presence of Factor V Leiden mutation is indicative.
• Genetic testing, which identifies the 1691G→A substitution using PCR, restriction enzyme digestion, and DNA electrophoresis.

Management

There is no cure for Factor V Leiden, so treatment focuses on preventing thrombotic complications. Routine anticoagulant use is not recommended for heterozygous individuals unless additional risk factors are present. However, anticoagulants are prescribed when a thrombotic event occurs. Temporary anticoagulation may be necessary during high-risk periods such as major surgery. Homozygous individuals or heterozygous individuals with additional thrombophilia should consider lifelong oral anticoagulation.

Epidemiology

Approximately 5% of Caucasians in North America have Factor V Leiden, with a higher prevalence among Caucasians compared to minority groups. Up to 30% of patients presenting with DVT or PE have this condition. The risk of developing a clot increases significantly with the inheritance of one or two copies of the mutation. Heterozygous individuals have a 4- to 8-fold increased risk, while homozygous individuals have up to an 80-fold increased risk. Acquired risk factors such as smoking, contraceptive use, and surgery further elevate the risk.

Women with Factor V Leiden face a higher risk of clotting during pregnancy or when using oestrogen-containing contraceptives. They may also have a slightly increased risk of preeclampsia, low birth weight babies, and pregnancy loss, though many may go through pregnancies without complications.

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Self-assessment MCQs (single best answer)

What is Factor V Leiden (FVL) thrombophilia?

Which city is Factor V Leiden named after?

What influences the variability of Factor V Leiden presentation among individuals?

Which of the following is NOT a symptom of Factor V Leiden?

What is the role of activated protein C (APC) in normal coagulation?

What kind of mutation is involved in Factor V Leiden?

Which test is NOT commonly used to diagnose Factor V Leiden?

What is the recommended management for heterozygous individuals with Factor V Leiden who have not had a thrombotic event?

What is the prevalence of Factor V Leiden among Caucasians in North America?

Which group faces a higher risk of developing clots when they have Factor V Leiden?