Factor V Leiden
Factor V Leiden (G1691A Variant)
What it is
Factor V Leiden is a genetic variant in the F5 gene — a single nucleotide change (G1691A) that substitutes glutamine for arginine at position 506 of the Factor V protein, a central component of the coagulation cascade. Under normal physiology, activated protein C (APC) inactivates activated Factor Va (and Factor VIIIa) by cleaving it at specific sites, including arginine 506 — this is a critical brake on coagulation that limits clot formation once a vessel injury has been repaired. The Leiden variant destroys the arginine 506 cleavage site, making Factor Va resistant to APC. The result is called APC resistance: the coagulation cascade generates thrombin and fibrin clot more readily, takes longer to shut down, and produces a prothrombotic state. Factor V Leiden is by far the most common inherited thrombophilia in populations of European descent — present in approximately 5% of the population as a heterozygous variant (one copy) and in approximately 0.02–0.1% as a homozygous variant (two copies). It was identified and characterised by Bertina and colleagues in 1994.
Why we measure it
Venous thromboembolism (VTE) — encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) — is the third most common cardiovascular condition after myocardial infarction and stroke, responsible for substantial morbidity and, in the case of PE, significant mortality. Factor V Leiden is identified in approximately 20–25% of all VTE cases and in approximately 50% of familial VTE cases, making it the single most important inherited contributor to venous thrombotic risk. Heterozygous Factor V Leiden increases VTE risk approximately 4–7-fold above the general population; homozygous Factor V Leiden increases risk approximately 80-fold. The risk is not uniformly expressed — most carriers never experience a VTE event — but it is dramatically compounded by additional prothrombotic exposures, and this is where knowledge of carrier status is most clinically important. Combined oral contraceptives containing oestrogen increase VTE risk approximately 3–4-fold in the general population; in heterozygous Factor V Leiden carriers, the combined risk is multiplicative rather than additive, producing an approximately 35-fold increase in VTE risk above the general population baseline. Pregnancy, surgery, prolonged immobility, long-haul air travel, obesity, and certain cancer diagnoses all add to this compounded risk. Knowing Factor V Leiden status changes clinical decision-making in each of these contexts: alternative contraceptive methods for carriers, prophylactic anticoagulation planning for surgical procedures, and informed risk stratification for major travel or immobility events. It also provides the basis for family screening if a VTE event does occur in a carrier.
Why once at enrollment
Factor V Leiden genotype is determined at conception and does not change. A single test at enrollment produces a lifetime result that informs clinical decisions across all subsequent prothrombotic exposures.
What movement means
Factor V Leiden testing produces a categorical genotype result. The G1691A variant is identified as heterozygous (one copy, GA genotype) or homozygous (two copies, AA genotype), compared with the normal non-carrier state (GG genotype). The clinical implications of each genotype are substantially different.
Non-Carrier (GG)
No Factor V Leiden variant
Normal Factor V function. No inherited increase in VTE risk from this variant. Standard risk management for thrombosis applies based on acquired risk factors (immobility, surgery, obesity, hormonal therapy) rather than inherited thrombophilia.
Bertina RM et al., Nature, 1994 — doi:10.1038/369064a0
Heterozygous (GA)
One copy; ~4–7x increased VTE risk
The most common carrier state (~5% of the population of European descent). VTE risk is 4–7-fold above baseline. Risk is significantly compounded by oestrogen-containing contraceptives (~35-fold above baseline), surgery, prolonged immobility, pregnancy, and obesity. These exposures warrant prospective risk discussion with a clinician. Alternative contraceptive options and pre-surgical anticoagulation planning should be considered.
Ridker PM et al., New England Journal of Medicine, 1995 — doi:10.1056/NEJM199504063321403
Homozygous (AA)
Two copies; ~80x increased VTE risk
Rare genotype (~0.02–0.1% of the population). Very high lifetime VTE risk. Most carriers will experience at least one thrombotic event. Prothrombotic exposures (oestrogen, surgery, immobility) carry very high absolute risk and require careful haematology input. Specialist review is recommended for all major clinical decisions involving thrombosis risk.
Ridker PM et al., New England Journal of Medicine, 1995 — doi:10.1056/NEJM199504063321403
In the protocol
References
- 1.
Bertina RM, Koeleman BPC, Koster T, et al.. “Mutation in Blood Coagulation Factor V Associated with Resistance to Activated Protein C.” Nature. 1994.
- 2.
Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. “Mutation in the Gene Coding for Coagulation Factor V and the Risk of Myocardial Infarction, Stroke, and Venous Thrombosis in Apparently Healthy Men.” New England Journal of Medicine. 1995.
- 3.
Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM, Rosendaal FR. “Increased Risk of Venous Thrombosis in Oral-Contraceptive Users Who Are Carriers of Factor V Leiden Mutation.” The Lancet. 1994.
- 4.
Cushman M. “Epidemiology and Risk Factors for Venous Thrombosis.” Seminars in Hematology. 2007.