Factor V Leiden: What Your Clotting Gene Means for Your Health
Understanding the most common inherited blood clotting disorder — and when it actually matters
By GenomeInsight Science Team
Key Takeaways
- Factor V Leiden (rs6025) is the most common inherited clotting disorder — ~5% of Europeans are heterozygous carriers
- Heterozygous carriers have 3-8× DVT risk; homozygous carriers have ~80× risk
- The most dangerous interaction is with estrogen-containing birth control (~35× DVT risk) — progestin-only methods are safe alternatives
- Most heterozygous carriers never develop clots — risk is highest when combined with other factors (surgery, pregnancy, immobilization)
- For travel, compression stockings reduce DVT risk by ~70% and are the most effective prevention
- Inform all healthcare providers, especially before surgery, pregnancy planning, or starting hormonal medications
What Is Factor V Leiden?
Factor V Leiden is the most common inherited thrombophilia (tendency to form blood clots). It's caused by a single nucleotide change in the F5 gene — specifically rs6025 (G→A) — which produces a variant form of coagulation Factor V protein that resists inactivation by activated protein C (APC).
In normal clotting, Factor V is a pro-coagulant protein that helps form clots when needed (e.g., after a cut). Once the clot has done its job, activated protein C (APC) cleaves Factor V to shut down the clotting cascade. The Leiden variant changes an amino acid at the APC cleavage site (R506Q), making Factor V resistant to this "off switch."
The result: a hypercoagulable state where the clotting cascade stays active longer than it should, increasing the risk of inappropriate clot formation — particularly in the deep veins of the legs (deep vein thrombosis, or DVT) and lungs (pulmonary embolism, or PE).
Factor V Leiden was discovered in 1994 by Rogier Bertina and colleagues at the University of Leiden in the Netherlands — hence its name.
Prevalence and Risk by Genotype
Factor V Leiden is remarkably common in people of European descent:
| Genotype | Frequency (European) | DVT/PE Risk | APC Resistance |
|---|---|---|---|
| GG (Normal) | ~90-95% | Baseline (1×) | Normal APC response |
| GA (Heterozygous) | ~5% (1 in 20) | 3-8× increased | Partial APC resistance |
| AA (Homozygous) | ~0.02-0.05% (1 in 2000-5000) | ~80× increased | Near-complete APC resistance |
Ethnicity matters: Factor V Leiden is found in approximately 5% of European-descent populations, 2% of Hispanic Americans, 1.2% of African Americans, and is very rare (<0.5%) in East Asian and sub-Saharan African populations.
Absolute risk perspective: Even though the relative risk increase sounds alarming, the absolute risk is more reassuring. The baseline annual risk of DVT in the general population is about 1 in 1,000. For a heterozygous carrier, that becomes roughly 3-8 in 1,000 per year — meaning a heterozygous carrier still has a >99% chance of NOT having a DVT in any given year.
For homozygous carriers, the situation is more serious. Lifetime DVT risk approaches 50-80%, and many experience their first clot before age 40.
When Should You Actually Worry?
Factor V Leiden alone — especially in heterozygous form — is often not enough to cause clots. Most clotting events occur when Factor V Leiden combines with additional risk factors. This is called the "multi-hit" hypothesis: you need your genetic predisposition PLUS one or more additional triggers.
Major additional risk factors that compound Factor V Leiden risk:
🔴 Oral contraceptives (birth control pills): Estrogen-containing birth control increases clotting risk ~4× on its own. Combined with heterozygous Factor V Leiden, the risk jumps to ~35× baseline — a synergistic, not merely additive, effect. This is perhaps the most clinically important interaction.
🔴 Hormone replacement therapy (HRT): Oral estrogen HRT increases DVT risk 2-4× in Factor V Leiden carriers. Transdermal (patch) estrogen appears significantly safer and may be preferred for carriers.
🔴 Surgery and immobilization: Major surgery, especially orthopedic procedures, combined with bed rest dramatically increases risk. Carriers should inform surgeons and may need extended prophylactic anticoagulation.
🔴 Pregnancy and postpartum: Pregnancy is a natural hypercoagulable state. Factor V Leiden carriers have 5-10× higher risk of pregnancy-related DVT compared to non-carriers. The postpartum period (first 6 weeks) is the highest-risk window.
🟡 Long-haul travel: Flights >4 hours increase DVT risk. For carriers, the risk is modestly elevated. Compression stockings, hydration, and movement are recommended.
🟡 Obesity: BMI >30 roughly doubles clotting risk independently, compounding genetic risk.
🟡 Smoking: Increases clotting risk through endothelial damage and should be avoided by carriers.
Birth Control, HRT, and Pregnancy Considerations
The intersection of Factor V Leiden and hormonal medications deserves special attention because it affects millions of women:
Birth Control Options for Factor V Leiden Carriers:
| Method | Risk Level | Notes |
|---|---|---|
| Combined pill (estrogen + progestin) | 🔴 High risk | ~35× DVT risk for heterozygous carriers — generally contraindicated |
| Patch / vaginal ring | 🔴 High risk | Same estrogen-related risk as the pill |
| Progestin-only pill (mini pill) | 🟢 Acceptable | No significant clotting risk increase |
| Hormonal IUD (Mirena) | 🟢 Acceptable | Localized progestin, minimal systemic absorption |
| Copper IUD | 🟢 No hormonal risk | Non-hormonal, no clotting impact |
| Depo-Provera (injection) | 🟡 Uncertain | Limited data; some concern about modest DVT increase |
| Implant (Nexplanon) | 🟢 Likely acceptable | Progestin-only; limited data but reassuring |
Pregnancy management:
- •Factor V Leiden carriers who are pregnant should be monitored by a maternal-fetal medicine specialist
- •Prophylactic anticoagulation (low-molecular-weight heparin) may be recommended, especially with personal or strong family history of VTE
- •The postpartum period (first 6 weeks) is the highest-risk time — extended anticoagulation may be warranted
- •Compression stockings during pregnancy and postpartum are recommended
HRT in menopause:
- •If HRT is needed, transdermal estrogen (patch) is strongly preferred over oral estrogen
- •Transdermal delivery avoids the "first-pass" liver effect that increases clotting factors
- •Studies suggest transdermal HRT does NOT significantly increase DVT risk, even in Factor V Leiden carriers
Travel Precautions for Carriers
Long-haul travel (flights, car rides, or train journeys >4 hours) modestly increases DVT risk in the general population. For Factor V Leiden carriers, the risk is further elevated, though still low in absolute terms for heterozygous carriers without other risk factors.
Evidence-based travel precautions:
✈️ Compression stockings — Grade I compression (15-20 mmHg) reduces DVT risk by ~70% during long flights. This is the single most effective preventive measure. Available at pharmacies without prescription.
✈️ Movement and hydration — Walk the aisle every 1-2 hours. Do ankle pumps and calf raises while seated. Drink water regularly and avoid alcohol, which is dehydrating.
✈️ Aisle seat — Choose an aisle seat for easier movement. Window seat travelers have higher DVT rates due to reluctance to move.
✈️ Avoid leg crossing — Crossing legs compresses veins and impedes blood flow.
✈️ Aspirin — Low-dose aspirin (81mg) is sometimes recommended before long flights, though evidence for DVT prevention specifically is modest. Aspirin primarily prevents arterial (not venous) clots.
✈️ Prophylactic anticoagulation — For high-risk individuals (homozygous carriers, or heterozygous with prior DVT), a single dose of low-molecular-weight heparin before long flights may be recommended by your doctor.
When to seek emergency care during/after travel:
- •Sudden leg swelling, pain, or warmth (especially one-sided)
- •Chest pain, sudden shortness of breath, or coughing up blood
- •These symptoms require immediate medical attention — DVT and PE are treatable emergencies
What to Tell Your Doctor
If your GenomeInsight report shows Factor V Leiden (rs6025 GA or AA), here's how to discuss it with your healthcare providers:
Information to share: 1. "My genetic test shows I carry the Factor V Leiden variant (rs6025) — [heterozygous/homozygous]" 2. Any personal history of blood clots, unexplained pregnancy complications, or recurrent miscarriages 3. Family history of DVT, PE, or clotting disorders 4. Current medications — especially hormonal contraceptives or HRT 5. Upcoming surgeries or planned immobilization
Questions to ask:
- •"Should I switch my birth control method?" (if using estrogen-containing contraception)
- •"Do I need any blood tests?" (protein C, protein S, antithrombin — to rule out additional thrombophilias)
- •"Should my close relatives be tested?" (siblings have 50% chance of carrying the same variant)
- •"What precautions should I take before surgery?"
- •"Do I need anticoagulation during pregnancy?"
Important caveats:
- •A consumer genotyping result should ideally be confirmed with clinical-grade testing before making major medical decisions
- •Factor V Leiden status alone — without personal/family history of clots — does NOT typically warrant long-term anticoagulation
- •Most heterozygous carriers live entirely normal lives without ever experiencing a clot
- •The value of knowing is primarily in *avoiding compounding risk factors* (especially estrogen-containing contraceptives) and being prepared for high-risk situations (surgery, pregnancy, immobilization)
Medical Disclaimer: This article is for educational purposes only and does not constitute medical advice. Genetic information should be interpreted in the context of your full medical history by a qualified healthcare provider. Never change medications without consulting your doctor.
References
- [1]Bertina RM et al. (1994). Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 369(6475):64-7.PubMed
- [2]Vandenbroucke JP et al. (2001). Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 344(20):1527-35.PubMed
- [3]Kujovich JL (2011). Factor V Leiden thrombophilia. Genet Med. 13(1):1-16.PubMed
- [4]Rosendaal FR (2005). Venous thrombosis: the role of genes, environment, and behavior. Hematology Am Soc Hematol Educ Program. 2005:1-12.PubMed
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