A common inherited change in the F5 gene that makes blood slightly slower to switch off clotting, raising the risk of deep vein thrombosis and pulmonary embolism. Most carriers never have a clot.
Blood clotting is a balancing act. Your body needs to be able to seal an injury quickly, and it needs to be able to stop once the job is done. Factor V Leiden is an inherited change that tips that balance slightly toward clotting — the "off switch" works less well than it should, so clot formation carries on a little longer than it would otherwise.
It is not a bleeding disorder and it is not the same as having thick blood. Most of the time it produces no symptoms at all and causes no trouble across an entire lifetime. Its significance is that it raises the chance of an abnormal clot forming in a vein, particularly in circumstances that already push in that direction.
The main concerns are clots in the venous system:
Less commonly, clots occur in veins in the brain, abdomen or elsewhere. Factor V Leiden has also been associated with a somewhat higher chance of recurrent pregnancy loss and, less consistently, with other pregnancy complications.
Factor V Leiden is the most common inherited clotting tendency in people of European descent: roughly 3–8% carry one copy. It is much less common in other ancestry groups. Carrying two copies is rare, on the order of 1 in 5,000 people.
The risk it adds is real but should be kept in proportion. In the general population, the chance of a first venous clot is around 1 in 1,000 per year. With one copy of factor V Leiden that rises to roughly 3–8 in 1,000 per year, and with two copies it can reach as high as about 80 in 1,000 per year. Put the other way round: only about 10% of people carrying the variant ever develop an abnormal clot at all.
Factor V Leiden rarely causes a clot by itself. It usually shows its hand when it combines with something else that raises clotting risk temporarily or permanently — surgery, a significant injury, a plaster cast, long immobility, pregnancy and the weeks after birth, cancer, obesity, smoking, increasing age, or estrogen-containing medicines. Two smaller risks stacked together can be much more than the sum of their parts, which is why knowing about it is most useful in advance of a high-risk situation.
The gene involved is F5. A single inherited copy is enough to have an effect, so the pattern is described as autosomal dominant — but with what geneticists call incomplete penetrance, meaning most people with the change never develop the condition it predisposes to. If one parent carries a copy, each child has a 50% chance of inheriting it. Two copies, inherited one from each parent, carry noticeably higher risk than one.
Factor V Leiden is usually looked for after something has happened rather than as routine screening: an unexplained clot, a clot at an unusually young age, clots that keep recurring, a clot in an unusual location, or a strong family history. Testing typically starts with a blood test that measures how well the blood resists a natural anticoagulant called activated protein C, and a positive or borderline result is confirmed by genetic testing of F5.
Screening people with no symptoms and no family history is generally not recommended, partly because knowing about it does not by itself change what most people should do. What a result can usefully inform is a conversation with a doctor about specific situations — planned surgery, pregnancy, long-haul travel, or choosing a form of contraception. Those decisions belong with a clinician who knows your history.
Gene and variant. F5 (OMIM 612309) on 1q24.2 encodes coagulation factor V. The factor V Leiden allele is NM_000130.5:c.1601G>A, p.Arg534Gln (rs6025). Legacy nomenclature calls this R506Q; the 28-residue offset reflects numbering from the mature protein rather than the initiator methionine. The associated phenotype is cataloged as thrombophilia due to activated protein C resistance (OMIM 188055; MONDO:0008560; ICD-10-CM D68.51).
Mechanism. Arg534 (legacy Arg506) is one of three activated protein C cleavage sites in activated factor V. Substitution to glutamine removes that cleavage site, so inactivation of factor Va by APC proceeds approximately tenfold more slowly. The result is a prolonged prothrombinase complex lifetime, increased thrombin generation and the laboratory phenotype of APC resistance. A secondary contribution comes from impaired function of factor V as an APC cofactor in the inactivation of factor VIIIa. The effect is prothrombotic in the venous circulation; association with arterial thrombosis is weak and inconsistent.
Epidemiology and effect size. Heterozygote prevalence is approximately 3%–8% in populations of European ancestry, with regional peaks of 10%–15% reported in southern Sweden and Greece, and it is uncommon in African, East Asian and Indigenous American populations. Homozygosity occurs in roughly 1 in 5,000. Relative risk of a first venous thromboembolism is approximately 3–8 fold for heterozygotes and reported as 9–80 fold for homozygotes, the wide range reflecting cohort selection. In absolute terms the annual incidence of first VTE in an unselected heterozygote is below 1% in the absence of additional risk factors. Roughly 90% of carriers never experience a thrombotic event.
Gene–environment and gene–gene interaction. Risk is multiplicative rather than additive with acquired triggers — surgery, trauma, immobilization, malignancy, pregnancy and the postpartum period, obesity, increasing age, and exogenous estrogen. Co-inheritance with prothrombin c.*97G>A (F2 G20210A, rs1799963), or with deficiency of antithrombin, protein C or protein S, produces substantially higher risk than either factor alone. Pseudohomozygosity — factor V Leiden in trans with an F5 null allele — produces a homozygous-appearing APC-resistance ratio with heterozygous genotype.
Laboratory diagnosis. First-line testing is a second-generation APC resistance assay performed on factor-V-deficient plasma, which is reliable in the presence of most anticoagulants and lupus anticoagulant and can flag pseudohomozygosity and non-Leiden causes of APC resistance. Abnormal results are confirmed by targeted genotyping of c.1601G>A. Genotyping alone is appropriate when the specific question is carrier status.
Obstetric associations. The association with recurrent early pregnancy loss is established, with roughly a two- to threefold increase reported; associations with pre-eclampsia, intrauterine growth restriction and placental abruption are reported but less consistent across studies, and routine thrombophilia screening in unselected pregnancy loss is not endorsed by major obstetric bodies.
Testing strategy. Indications generally include unprovoked or recurrent VTE, VTE at a young age, VTE at an unusual site, and evaluation of first-degree relatives in specific clinical contexts. Population screening of asymptomatic individuals is not recommended, since carrier identification rarely alters management in the absence of an event and confers a low absolute risk. Anticoagulation decisions — including duration after an event and peripartum or perioperative prophylaxis — are individualized clinical judgments outside the scope of this page.
Inheritance. Autosomal dominant with incomplete penetrance; homozygotes have a substantially greater risk than heterozygotes, consistent with a gene-dosage effect.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Factor V Leiden Thrombophilia comes down to these specific, well-studied positions — not a diagnosis.
Research-derived gene–drug associations only — not a prescription, dosing guide, or medical advice. Always follow your prescriber's guidance.
| Gene | Drug | What the research shows |
|---|---|---|
| F5 | Combined hormonal contraceptives (estrogen-containing pills, patches, rings and injections) | Estrogen-containing contraception raises venous clot risk on its own, and in someone who also carries factor V Leiden the two effects multiply rather than simply add, producing a substantially higher risk than either factor alone. US CDC Medical Eligibility Criteria place combined hormonal contraceptives in category 4 — an unacceptable health risk — for people with a known thrombogenic mutation such as factor V Leiden. The same guidance states that routine screening for these mutations before starting contraception is not recommended, and the wider thrombophilia-screening literature gives the reason: the variant is uncommon and screening everyone yields little benefit for its cost. This is background information about a documented gene-drug interaction. It is not a recommendation to start, stop or switch any contraceptive; that decision belongs with your clinician. (CDC US Medical Eligibility Criteria for Contraceptive Use — combined hormonal contraceptives, thrombogenic mutations (category 4). PharmGKB/ClinPGx carries a clinical annotation for the F5 variant with hormonal contraceptives (evidence level 2A); there is no CPIC prescribing guideline for F5. Background evidence: Mohllajee AP et al., systematic review of hormonal contraceptive use in women with thrombogenic mutations, Contraception 2006, PMID 16413847.) |
For most carriers, not very. Only about 10% of people with the variant ever develop an abnormal clot. Annual risk of a first clot is roughly 3-8 per 1,000 for someone with one copy, against about 1 per 1,000 in the general population. Two copies carry considerably higher risk, reported as high as about 80 per 1,000 per year.
One copy is common and adds a moderate increase in risk. Two copies are rare, around 1 in 5,000 people, and add substantially more. Because a single copy is enough to have an effect, the inheritance is called autosomal dominant, but the effect clearly gets stronger with a second copy.
It does not rule any of those out by itself. What it does is change the calculation in situations that already raise clotting risk, which is exactly the sort of thing worth discussing with your doctor in advance. Combined hormonal contraception in particular is one area where established guidance treats a known thrombophilia as significant.
Not automatically. Testing people with no symptoms and no clot history is generally not recommended, because a positive result rarely changes what someone should do day to day. Testing is more likely to be useful where there is a personal or strong family history of clots, and a doctor or genetic counselor can advise on whether it applies in your family.
Usually in two steps: a blood test measuring resistance to activated protein C, followed by genetic testing of the F5 gene to confirm the c.1601G>A (R506Q) variant. Genetic testing alone is used when the only question being asked is whether someone carries the variant.
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