What is Factor V Leiden?
Factor V Leiden is a specific genetic mutation (G to A at nucleotide 1691 of the factor V gene, resulting in R506Q amino acid substitution) that makes factor V resistant to inactivation by activated protein C, creating the most common inherited thrombophilia and significantly increasing the risk of venous thromboembolism. 1, 2
The Molecular Defect
Factor V Leiden involves a single point mutation that substitutes glutamine for arginine at position 506 (previously referred to as position 534 in newer nomenclature), which is one of three critical cleavage sites where activated protein C (APC) normally inactivates factor Va 1, 2. This initial cleavage at position 506 is essential for exposing the other two cleavage sites (positions 306 and 679) for rapid factor V inactivation 1. When this site is mutated, factor Va persists longer in circulation, generating excessive thrombin and creating a hypercoagulable state 2.
The mutation accounts for 85-95% of all cases of APC resistance, which is the most common recognized coagulation abnormality among patients with venous thromboembolism 1.
Population Distribution and Prevalence
The mutation shows striking ethnic variation:
- Caucasians: ~5% carry the heterozygous form (5.1% in US Europeans) 1, 2
- Hispanic-Americans: ~2.0% 2
- African-Americans: ~1.2% 2
- Africans and Asians: virtually absent 1
- Middle Eastern populations: highest frequency at ~3.9% 2
Homozygosity is rare: approximately 65 per 100,000 in Europeans, 10 per 100,000 in Hispanics, and 4 per 100,000 in African Americans 2.
Thrombotic Risk Profile
The mutation confers dramatically different risks based on whether you carry one or two copies:
Heterozygotes (one copy):
- 6-8 fold increased risk of venous thromboembolism 1, 2
- ~10% lifetime risk of VTE 1
- Found in 11-20% of all patients presenting with first VTE 1
- Up to 40% of patients under age 50 with recurrent thrombosis carry this mutation 1
Homozygotes (two copies):
- 80-fold increased risk of VTE 1, 2
80% lifetime risk of VTE 1
- 15 VTE events per 1000 persons per year (compared to 2.9 for heterozygotes) 2
Clinical Manifestations
The primary manifestations are deep vein thrombosis and pulmonary embolism, but thrombosis can occur in unusual sites including hepatic, mesenteric, and cerebral veins 1.
Important clinical context: The first VTE episode in Factor V Leiden carriers typically occurs after age 50, so testing should not be limited to young patients 1. In one study, 26% of men over age 60 with first idiopathic VTE had Factor V Leiden 1.
Arterial Thrombosis
Factor V Leiden is not generally associated with arterial thrombosis, myocardial infarction, or stroke 1. The critical exception is myocardial infarction in young female smokers under age 45-50, where the combination increases relative risk 32-fold 1.
Pregnancy Complications
Factor V Leiden increases risk for:
- Recurrent fetal loss (possibly due to placental thrombosis) 1
- Severe preeclampsia 1
- Placental abruption 1
- Intrauterine fetal growth retardation 1
- Stillbirth 1
However, the probability of successful pregnancy outcome remains high overall 3.
Inheritance Pattern
Factor V Leiden exhibits autosomal dominant or semidominant inheritance 1. Both heterozygotes and homozygotes face increased VTE risk, with homozygotes at substantially greater risk 2. A positive family history of VTE increases risk 2.9-fold, and if a relative had VTE before age 50, risk increases 5-fold 2.
Diagnostic Testing
Two methods exist:
- Functional APC resistance assay - casts a wider net but lacks specificity, affected by pregnancy, oral contraceptives, acute phase reactants, and cannot be used during anticoagulation 1
- Direct DNA testing for R506Q mutation - highly specific, simple, inexpensive, can be performed during anticoagulation, and distinguishes heterozygotes from homozygotes 1
The mutation involves only a single nucleotide change, making molecular genetic testing straightforward and definitive 1.
Key Clinical Pitfall
Fetal testing and routine newborn screening are NOT indicated because Factor V Leiden-associated thrombophilia is an adult-onset disorder of low penetrance 1. Population screening is also not recommended 1.