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Your blood has a built-in braking system. Every time a clot forms to stop a cut from bleeding, a set of proteins steps in to shut the process down once the job is done. Factor V Leiden is a single inherited gene change that weakens one of those brakes, leaving your clotting system running longer than it should. The result is blood that clots a little too easily, raising your risk for deep vein clots and pulmonary embolism, sometimes with no warning.
What makes this mutation worth knowing about is how common it is and how invisible it stays. Roughly 5% of people with European ancestry carry at least one copy, yet most will never be told unless they develop a clot or a family member does. Standard blood tests do not detect it. Knowing your status lets you make informed choices about birth control, hormone therapy, surgery, travel, and pregnancy, well before a clot forces the conversation.
Factor V is a protein made mostly by the liver. When you get a cut, factor V speeds up the clotting process by helping another clotting protein, called factor Xa, convert prothrombin into thrombin, the enzyme that builds the clot. Once the clot is big enough, your body sends in activated protein C (APC) to chop up factor V and shut down thrombin production. This is the braking mechanism.
The Leiden mutation changes a single amino acid at one of the exact spots where APC is supposed to cut. The result is a factor V protein that resists being shut off. It persists in the bloodstream roughly ten times longer than normal factor V, continuing to drive thrombin generation after the brake should have engaged. The mutation does not make you produce more factor V or less of it. It produces a normal amount of a protein that simply does not respond to the normal shutdown signal.
Unlike most blood biomarkers, Factor V Leiden is not measured in concentrations that go up or down. It is a yes-or-no genetic test. You are either a non-carrier (no copies of the mutation), a heterozygous carrier (one copy, inherited from one parent), or a homozygous carrier (two copies, one from each parent). Your status is fixed at birth and never changes. This means a single test provides a lifetime answer.
The primary risk tied to Factor V Leiden is venous thromboembolism (VTE), which includes deep vein thrombosis (DVT, a clot in a deep vein, usually in the leg) and pulmonary embolism (PE, when a clot breaks off and travels to the lungs). The largest long-term study followed over 9,200 Danish adults for 23 years and found that heterozygous carriers faced about 2.7 times the risk of VTE compared to non-carriers. Homozygous carriers faced about 18 times the risk.
A Swedish study of nearly 4,900 people over about 16 years confirmed these findings: heterozygous carriers had roughly 1.8 times the VTE risk, while homozygous carriers had about 6.5 times the risk. That study also confirmed what researchers call the "Factor V Leiden paradox." Heterozygous carriers had a stronger association with DVT than with pulmonary embolism, suggesting the mutation may preferentially promote clots that stay in the legs rather than breaking loose.
| Who Was Studied | What Was Compared | What They Found |
|---|---|---|
| 9,253 Danish adults over 23 years | VTE risk in heterozygous vs. non-carriers | About 2.7 times higher risk in carriers |
| Same Danish cohort | VTE risk in homozygous vs. non-carriers | About 18 times higher risk |
| 4,890 Swedish adults over ~16 years | VTE risk in heterozygous vs. non-carriers | About 1.8 times higher risk |
What this means for you: the relative risk increase sounds dramatic, but the absolute risk stays modest for heterozygous carriers. The annual chance of a first clot is roughly 0.5%, and only about 10% of heterozygous carriers ever develop a clot in their lifetime. For homozygous carriers, lifetime VTE risk approaches 80 to 100%, making it far more urgent to know your status.
Factor V Leiden does not only affect the legs. Carriers face elevated risk for clots in unusual sites, including the veins of the brain (cerebral venous thrombosis, about 2.7 times higher odds), the upper arms (about 6 times higher risk), and the superficial veins just beneath the skin (about 6 times higher risk). Clots in the veins of the liver, eyes, and kidneys have also been reported in carriers.
Women who carry Factor V Leiden face roughly 2 to 3 times the risk of recurrent pregnancy loss, particularly second and third trimester losses. Possible connections to preeclampsia, fetal growth restriction, and placental abruption have been studied, though these links remain less firmly established. Homozygous carriers face about 34 times the usual risk of VTE during pregnancy.
Compound carriers, those with both Factor V Leiden and the prothrombin G20210A mutation, face up to 47 times the pregnancy-related VTE risk. For women planning pregnancy who have a family history of clotting, knowing their genetic status can directly shape decisions about preventive blood thinners during pregnancy and postpartum.
The relationship between Factor V Leiden and arterial events (heart attacks, strokes) is much weaker than its connection to venous clots. A large meta-analysis combining over 66,000 coronary disease cases and over 91,000 controls found only a modest 17% increase in coronary disease risk per copy of the mutation. A study of nearly 70,000 patients with established heart disease found no meaningful link between carrying Factor V Leiden and subsequent heart attacks, strokes, or cardiovascular death.
There may be a stronger signal in younger adults. A meta-analysis of arterial events found that the association was more pronounced in people under 55, suggesting that Factor V Leiden may contribute more to early arterial events than to late-life cardiovascular disease. But the net effect on arterial disease is small compared to traditional risk factors like high blood pressure and high cholesterol.
Factor V Leiden rarely acts alone. The mutation becomes most dangerous when it combines with other risk factors that independently promote clotting. In the Danish cohort study, heterozygous carriers who were over 60, smoked, and had a BMI above 30 had a 10-year VTE risk of about 10%. Homozygous carriers with the same profile faced about a 51% chance of a clot within 10 years.
An Icelandic population study found that homozygous Factor V Leiden carriers lived about 4.5 fewer years on average compared to non-carriers, with about 7.6 times the odds of VTE. Heterozygous carriers did not show a statistically meaningful reduction in lifespan, consistent with the relatively modest absolute risk increase in single-copy carriers.
One of the most common questions after a first VTE is whether Factor V Leiden means it will happen again. The answer is less alarming than many expect. A meta-analysis of recurrence data found that heterozygous carriers had only about a 56% increase in the odds of a second clot. Homozygous carriers had about a 2.65-fold increase. A separate study found nearly identical recurrence curves for heterozygous carriers and non-carriers after stopping anticoagulation, suggesting that heterozygous status alone is a weak predictor of recurrence.
This matters because it means most heterozygous carriers do not need lifelong blood thinners after a provoked first VTE (one caused by a clear trigger like surgery or a long flight). The decision about how long to continue anticoagulation depends more on whether the initial clot was provoked or unprovoked, and on total bleeding risk, than on Factor V Leiden status alone.
There are two ways to test for Factor V Leiden. The first is a functional screening test called the activated protein C resistance (APCR) assay. It measures how well your blood responds to activated protein C. If your blood resists APC's slowdown signal, the test flags you for follow-up. The second is direct DNA-based genetic testing using PCR (a technique that amplifies a specific stretch of DNA), which identifies the exact R506Q mutation. DNA testing is definitive and can distinguish between heterozygous and homozygous carriers, a distinction that matters because homozygotes face substantially higher risk.
The APCR functional test has good but imperfect accuracy, with sensitivity of roughly 89 to 94% and specificity of 71 to 84% depending on the cutoff used. It is gender-dependent: women tend to have lower APCR ratios than men, meaning about 35% of women without the mutation fall below the standard cutoff compared to 18% of men. The DNA test has near-perfect analytical accuracy and is unaffected by medications, illness, or any physiological state.
If you are tested using the functional APCR screening method rather than the DNA test, several factors can produce unreliable results. Direct oral anticoagulants (DOACs) like rivaroxaban and apixaban can make a true positive look negative, masking the mutation. Direct thrombin inhibitors like dabigatran can also distort results. Warfarin affects the assay as well. Lupus anticoagulant antibodies, pregnancy, oral contraceptives, acute thrombosis, and acute inflammation can all reduce the accuracy of the functional test.
None of these factors affect the DNA-based genetic test. Because your DNA sequence does not change with medications, illness, pregnancy, diet, exercise, or time of day, the genetic test can be drawn under any circumstances. This is why most guidelines now recommend DNA testing as the preferred method, especially if you are currently on blood thinners or acutely ill.
Factor V Leiden is overwhelmingly a mutation of European descent. About 5.1% of European Americans carry at least one copy. In Hispanic Americans, the rate drops to about 2%. In African Americans, about 1.2%. In Asian Americans, it is rare at roughly 0.45%. The highest frequencies in the world are found in southern Sweden and Greece, where 10 to 15% of the population carries the mutation. The mutation itself carries the same risk regardless of ethnic background; only how commonly it occurs differs across populations.
Because Factor V Leiden is a genetic mutation, not a fluctuating blood level, you only need to be tested once. Your result applies for life. There is no concept of serial trending or retesting to see if your status has changed. The within-subject variability of the APCR functional test is remarkably low (about 1.5%), reflecting the fixed genetic nature of what is being measured.
The one scenario where repeat testing may be warranted is if your initial result came from a functional APCR screening test performed under suboptimal conditions, such as while you were on anticoagulants, acutely ill, pregnant, or taking oral contraceptives. In that case, the recommendation is not to repeat the APCR test, but to proceed directly to DNA-based testing for a definitive answer.
Factor V Leiden is best interpreted alongside these tests.