Factor V Leiden and a 23andMe “Variant Detected” Result: What the Real Risk Is

Factor V Leiden and a 23andMe “Variant Detected” Result: What the Real Risk Is

This article is for educational purposes only. It is not a substitute for advice from a licensed physician, board-certified medical geneticist, or board-certified genetic counselor. For any decisions about testing, treatment, or care, consult a qualified clinician. In emergencies, call 911.

Bottom line: A direct-to-consumer label like “Factor V Leiden — variant detected” sounds alarming, but it overstates your real danger. Factor V Leiden is a common, well-studied variant with low penetrance (meaning most carriers never develop the condition). Large cohort studies show heterozygous carriers face roughly a 3-to-8-fold higher relative risk of a blood clot, yet the absolute risk stays low — about 4 to 5 clots per 1,000 carriers each year, versus about 1 per 1,000 in non-carriers. Most people with one copy never have a clot. Crucially, the American Society of Hematology’s 2023 guideline does not recommend routine thrombophilia screening of people without symptoms, and asymptomatic carriers do not need lifelong blood thinners.

What you’ll learn:

• What the F5 gene variant actually does inside your body, and how it passes to children.
• The difference between a scary relative risk number and your true absolute risk.
• When a 23andMe result should be confirmed by a real medical test — and when it changes nothing.
• What professional societies now say about screening, prevention, and treatment.

1. What Factor V Leiden Is and How It’s Inherited

Factor V Leiden is a single spelling change in the F5 gene on chromosome 1. The change is written as c.1601G>A, p.R506Q. In plain terms, one DNA “letter” is swapped, which alters one protein.

That protein is Factor V, a normal part of your blood-clotting system. Normally, a natural brake called activated protein C (APC) switches Factor V off after a clot forms. The Leiden variant makes Factor V resistant to that brake — a state called APC resistance (meaning your “off switch” for clotting works less well). So clotting turns off more slowly than it should.

Think of it like a faucet with a slightly stiff shut-off valve. Water still flows normally, but the valve takes a little longer to close.

It is worth stressing what the variant does not do. It does not thicken your blood at rest, and it does not mean a clot is forming right now. Under ordinary conditions your blood behaves normally. The difference only shows up when your clotting system is switched on — after an injury, surgery, or another trigger — and then takes slightly longer to switch back off. That is why carriers can go decades, or a whole lifetime, without a single problem.

The variant follows an autosomal dominant, dose-dependent pattern. Autosomal dominant means one copy from either parent is enough to raise risk. Dose-dependent means two copies raise it much more than one:

How many copies	Term	Effect
One copy	Heterozygous (a “carrier” — you have one altered copy and one normal copy)	Moderately higher clot risk
Two copies	Homozygous (both copies altered)	Substantially higher clot risk

Because a child inherits one F5 copy from each parent, a single heterozygous parent gives each child about a 50% chance of inheriting the variant. This researcher-defined mechanism was first mapped in 1994 by the Leiden Thrombophilia Study, which named the variant. If you want to understand your own inheritance pattern, a genetic counselor (find one through nsgc.org) can walk your family through it.

It helps to know how common this variant is. Factor V Leiden is the most common inherited thrombophilia (an inborn tendency to form clots) in people of European ancestry, found in roughly 3-8% of that group. It is much rarer — about 1 in 1,000 — in people of African, Native American, or Asian descent. So if your sibling tested positive, the odds that you carry it too are meaningfully higher than in the general public, but a shared result is far from certain.

The 1994 discovery mattered because, before it, doctors could see that some families clotted more without knowing why. Bertina and colleagues showed the exact site — the amino acid at position 506, where the natural brake normally cuts Factor V — is changed. That single insight turned “unexplained family clotting” into a testable, named condition and made counseling possible. In the original Leiden study, the variant showed up in a large share of patients who had a first, unexplained vein clot.

Section recap: Factor V Leiden is one DNA change in the F5 gene that weakens your clotting “off switch.” One copy raises risk moderately; two copies raise it much more; each child of a carrier has about a 50% chance of inheriting it.

2. How Big Is the Risk, Really? (Relative vs. Absolute)

Here is where a DTC report can mislead you. A “3-to-8-fold increased risk” sounds terrifying. But that is a relative risk — it multiplies a starting number that is already small.

The starting number matters. In the general population, the baseline rate of venous thromboembolism (VTE — a blood clot in a vein, such as a deep vein thrombosis or a clot that travels to the lungs) is roughly 1 per 1,000 people per year. Multiplying a small number by 3 to 8 still leaves a modest number.

Here is what the research actually shows across major cohorts:

Group	Relative risk of VTE	Absolute risk (about)
Non-carrier (general population)	1x (baseline)	~1 clot per 1,000 people per year
Heterozygous carrier	~3-8x	~4-5 clots per 1,000 carriers per year
Homozygous carrier	up to ~50-80x	Substantially higher; needs specialist assessment

A family-based cohort put real numbers on this: heterozygous carrier relatives had a VTE rate of about 0.4-0.5% per year, versus about 0.1% per year in non-carrier relatives. Over a lifetime, that translates to an estimated 5-10% lifetime risk for carriers, versus roughly 1-3% for non-carriers.

To make that concrete, imagine 1,000 heterozygous carriers followed for a year. At a rate of about 0.4-0.5%, roughly 4 or 5 of them would have a clot — meaning about 995 would not. That is the number a DTC label rarely shows. The relative-risk headline focuses on the handful who clot; the absolute figure keeps the far larger group who stay well in view.

Homozygous carriers are a genuinely different case. Their relative risk can reach roughly 50-to-80-fold, so their absolute annual risk is meaningfully higher and their care is individualized. If a clinical test confirms two copies, that is a clear reason to see a hematologist rather than rely on general reassurance.

Two points reframe the fear:

• Most heterozygous carriers never have a clot. Prospective studies that followed carriers forward in time — like the LITE cohort — found even lower risk than clinic-based studies, because clinics see the sickest people.
• Penetrance depends on triggers. VTE is a “multicausal disease”. Carrier status alone is a modest risk factor; clots usually happen when the variant combines with a trigger like surgery, immobility, pregnancy, or estrogen.

Why do clinic studies and population studies disagree? Clinic-referral studies count people who already came in with a clot, so they tend to report higher numbers. Prospective general-population cohorts like LITE follow ordinary carriers forward and catch the many who never get sick. The MEGA case-control study, which compared thousands of first-clot patients against healthy controls, landed in the middle: about a 3-to-5-fold relative risk for heterozygous carriers. Reading these designs together gives a fuller, calmer picture than any single scary figure.

Age matters too. Baseline clot risk climbs steeply as people get older. A several-fold multiplier on a very small young-adult risk is still small; the same multiplier later in life produces a somewhat larger — but still modest — absolute number. This is one more reason a personalized read from a clinician beats a one-size-fits-all label.

Analogy: carrying the variant is like living in a region that gets occasional storms. It raises the odds of a flood, but you also need heavy rain (a trigger) at the same time. This is exactly why a genetic counselor or physician interprets the number for you, not a search result.

Section recap: The scary multiplier is a relative risk applied to a small baseline. In absolute terms, carriers face about 4-5 clots per 1,000 per year, and most carriers never have a clot at all.

3. Testing Options: DTC vs. Clinical Diagnostic

A 23andMe result and a doctor-ordered test are not the same thing. Understanding the difference protects both your health and your wallet.

• DTC (direct-to-consumer) susceptibility reports — like the 23andMe Health Predisposition report — screen for the F5 R506Q variant. They are a screening signal, not a clinical diagnosis. Results should be confirmed before you act on them.
• Clinical diagnostic testing — ordered by a physician or NSGC-certified genetic counselor — uses either targeted F5 genotyping (reading the exact gene) or a functional APC-resistance clotting assay (a lab test that measures how well your blood resists the APC brake).

Here is a side-by-side comparison:

Feature	DTC test (e.g., 23andMe)	Clinical diagnostic test
Who orders it	You	Physician or genetic counselor
Lab standard	Consumer-grade screen	CLIA-validated (a US quality standard for clinical labs)
Examples	23andMe Health Predisposition	Invitae, Color/Labcorp panels
Insurance	Usually out of pocket	Often covered when clinically indicated
Use	A signal to discuss	Confirms carrier status

Why confirm at all if the variant is well known? Two reasons. First, consumer chips read specific spots and can occasionally miscall a single position; a clinical lab re-tests with methods built for medical decisions. Second, a clinical test can add the functional APC-resistance assay, which measures how your blood actually behaves rather than only reading the gene. Together they give a physician a result solid enough to counsel on.

The practical rule: a positive DTC result should be confirmed diagnostically before you make any medical decision. Bring your report to your primary care physician or a genetic counselor (nsgc.org); do not treat a consumer report as a final answer. That said, “confirm before acting” does not mean “panic and test tomorrow.” For someone with no symptoms and no clot history, confirmation is often a calm, planned conversation. As the next section explains, the result frequently changes nothing about daily care.

Section recap: A DTC report is a screening signal, not a diagnosis. Confirm any positive result with a CLIA-validated clinical test, ordered through your doctor or a genetic counselor, before acting.

4. What Your Result Actually Means Clinically

People often confuse three very different things: a diagnosis, a risk signal, and an uncertain finding. Getting this straight lowers anxiety.

• A diagnostic finding confirms you carry the variant. That is confirmed carrier status, not a disease.
• A risk/susceptibility signal (like a DTC result) suggests the variant may be present and points you toward confirmation.
• A variant of uncertain significance (VUS — a genetic change whose effect is not yet known) is different again. Factor V Leiden is not a VUS; it is a well-characterized, pathogenic-but-low-penetrance variant.

The key message: being a carrier is a risk factor, not a disease diagnosis. For an asymptomatic person with no clot history, a positive result usually does not change day-to-day medical management. The CDC states plainly that having Factor V Leiden is a risk factor for DVT and pulmonary embolism, not a disease — and most carriers never develop a clot.

Think of it like a smoke detector that beeps once. It signals you should pay attention to fire safety; it does not mean your house is on fire.

It is also worth knowing what “pathogenic-but-low-penetrance” means in practice. “Pathogenic” means the variant can contribute to disease; “low penetrance” means it does so in only a minority of carriers. Both parts are true at once. This is different from many single-gene disorders where a variant almost always causes disease. Factor V Leiden sits in a gentler category — a nudge to your risk, not a verdict.

You genuinely need a specialist — a hematologist or genetic counselor — in a few clear situations. These include a personal or strong family clot history, a homozygous result, pregnancy planning, or multiple thrombophilias at once. For routine “variant detected with no symptoms,” a conversation with your primary care physician is usually enough. Warning signs that always warrant urgent care, carrier or not, include a swollen, painful calf, or sudden shortness of breath or chest pain — possible signs of a clot. When in doubt about testing decisions, a counselor at nsgc.org can help you decide.

Section recap: Carrier status is a risk factor, not a disease. For an asymptomatic person, a positive result usually does not change management — but a clot history, homozygosity, or pregnancy planning warrants specialist input.

5. Prevention and Early Detection: Manage Triggers, Not a Pill

The evidence points to situational risk reduction, not lifelong medication. Because clots usually need a genetic risk factor plus a trigger, managing the triggers is where carriers gain the most.

Watch for these high-risk windows:

• Surgery and prolonged immobility — clot risk climbs when you cannot move.
• Long-haul travel — stay hydrated, walk the aisle, and flex your calves on long flights.
• Pregnancy and the weeks after delivery — a natural high-clotting window.
• Estrogen-containing contraceptives and hormone therapy — these raise VTE risk on their own and act synergistically with Factor V Leiden, compounding it.

That last point deserves shared decision-making. Estrogen-containing birth control raises clot risk on its own, and in a Factor V Leiden carrier the two factors combine so the risks stack rather than simply add. That does not mean estrogen is forbidden for every carrier; it means the choice deserves a real conversation about alternatives such as progestin-only or non-hormonal methods. The same synergy logic applies to hormone therapy around menopause.

Sometimes a clinician recommends short-term, situation-specific prevention. This can apply to major surgery or a hospital stay with prolonged bed rest. Options include compression or a brief course of a blood thinner during the risky window. That is very different from daily lifelong medication. Importantly, there is no evidence supporting routine preventive blood thinners in asymptomatic carriers during normal daily life. The goal is awareness during high-risk windows, not a pill every morning.

Analogy: you do not wear a life jacket at your desk. You put it on before you get in the boat. Prevention here means being ready for the risky moments. A genetic counselor or physician (nsgc.org) can map your personal high-risk windows.

Section recap: Prevention is situational, not a daily pill. Stay alert during surgery, immobility, travel, pregnancy, and estrogen use — and discuss contraception choices with your clinician. Routine anticoagulation for asymptomatic carriers is not recommended.

6. The Latest Treatment Landscape: The DOAC Era

If a carrier does have a clot, treatment has changed dramatically. The field has shifted from warfarin (an older blood thinner needing frequent blood tests) to direct oral anticoagulants (DOACs — newer pills that thin the blood without routine monitoring).

Both the ASH 2020 guideline and the CHEST 2021 update recommend DOACs over warfarin as first-line for most VTE. Warfarin works, but it needs regular blood draws and interacts with many foods and medicines. DOACs generally do not require that routine monitoring, which is a big part of why guidelines now prefer them for most people. Here are the approved DOACs with their regulatory dates:

Drug (brand)	FDA approval	Health Canada
Rivaroxaban (Xarelto)	2011-07-01	Authorized 2008
Apixaban (Eliquis)	2012-12-28	Authorized 2011
Dabigatran (Pradaxa)	2010-10-19	—
Edoxaban (Savaysa / Lixiana)	2015-01-08	—

Now the most reassuring part for carriers. Being a Factor V Leiden carrier does not, by itself, require indefinite anticoagulation. Treatment duration depends on whether the clot was provoked (triggered by something temporary like surgery) or unprovoked, and on your bleeding risk — not on your carrier status alone. For a first clot provoked by a temporary trigger, guidelines suggest a limited course, often 3-6 months, rather than lifelong therapy.

Why does “provoked versus unprovoked” matter so much? A clot after surgery or a long cast is like a fire started by a candle you have since blown out. Remove the trigger and the danger largely passes, so a limited course often suffices. A clot with no clear trigger is more like a fire with no obvious cause, so the risk of another may persist and longer treatment may be weighed. Both guidelines stress that this judgment rests on the event and bleeding risk, with carrier status as just one input among many.

One caution for carriers who search online: older articles sometimes imply that any inherited thrombophilia means lifelong blood thinners. The current ASH and CHEST guidance explicitly moves away from that. Any anticoagulation decision belongs with a physician or hematologist, ideally in shared decision-making, with periodic reassessment as your situation changes.

Section recap: DOACs (rivaroxaban, apixaban, dabigatran, edoxaban) are now first-line over warfarin. Carrier status alone does not mandate lifelong treatment; duration depends on whether the clot was provoked and on bleeding risk.

7. Family Implications and Cascade Testing

Cascade testing means that once one family member (the “proband”) tests positive, first-degree relatives may consider testing too. It sounds obvious — but the professional-society view is more nuanced.

Consider the trade-offs:

• A positive result rarely changes management for an asymptomatic relative, since carriers usually need no treatment.
• It can cause anxiety and insurance concerns without a clear medical benefit.
• The ASH 2023 guideline generally recommends against routine testing of asymptomatic relatives.

So this is a shared-decision-making conversation, not automatic testing of everyone. Some relatives may reasonably choose testing — for example, a sister planning pregnancy or considering estrogen contraception, where the result could inform choices. Others may prefer not to know.

The family-cohort data support this measured approach. The excess absolute risk for a heterozygous relative is modest, about 0.4-0.5% per year. That is why testing every relative rarely changes anyone’s care. Homozygous relatives or those with additional thrombophilias are a different story and merit individualized specialist assessment.

There is also a practical downside worth naming. A positive result on file can raise insurance questions for a relative who did not need the information in the first place (see the next section). The medical benefit for an asymptomatic person is usually small. So the ASH 2023 panel judged that reflexive testing of every first-degree relative does more harm than good in most families. The better path is targeted. A relative with a specific decision on the horizon — such as pregnancy or starting estrogen contraception — may reasonably choose testing after counseling. Others may skip it entirely.

Analogy: telling a relative to test “just in case” is like handing someone a weather forecast for a trip they may never take. Useful for some, unnecessary worry for others. A genetic counselor (nsgc.org) can guide each relative’s decision.

Section recap: Cascade testing is a shared decision, not a default. Because a positive result rarely changes management for asymptomatic relatives, professional guidance advises against routine testing of everyone.

8. Psychosocial Impact, GINA, and Insurance

A genetic label carries emotional weight, and it raises fair questions about privacy and insurance. Knowing the law helps you decide before you test. This matters because, unlike a medical decision you can revisit, a result on file cannot be unlearned. Thinking through the insurance angle in advance is one of the few parts of this whole topic where timing is genuinely in your control.

In the United States, the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from using your genetic information against you. But GINA has a critical gap you must understand:

Insurance / setting	Protected by GINA?
Health insurance	Yes — cannot use genetic info
Employment	Yes — employers cannot use it
Life insurance	No — not covered
Disability insurance	No — not covered
Long-term-care insurance	No — not covered

So GINA does not cover life, disability, or long-term-care insurance — a real gap to weigh before pursuing clinical diagnostic testing. Canada offers broader protection. The Genetic Non-Discrimination Act (2017) bars requiring genetic tests or disclosure of results as a condition of services or contracts, including insurance. The Supreme Court of Canada upheld it in 2020.

One practical sequence some families consider involves timing. If you are weighing life or disability insurance, you might complete those applications before undergoing clinical diagnostic testing. GINA does not shield those products. This is a personal, non-medical decision, and a genetic counselor can lay out the trade-offs without pressuring you either way. The key point is simply to know the gap exists before you decide.

On the emotional side, remember the reframing throughout this article: a susceptibility label is not a diagnosis. Research consistently frames Factor V Leiden as a low-penetrance risk factor most carriers live with uneventfully. Deciding whom to tell in your family is personal, and there is no single right answer. Some carriers find that sharing helps relatives make informed choices around pregnancy or contraception; others prefer to wait. A genetic counselor (nsgc.org) can help you think through both the disclosure and the timing of any diagnostic testing.

Section recap: GINA protects health insurance and employment but not life, disability, or long-term-care insurance; Canada’s 2017 law is broader. Weigh these gaps, and lean on a genetic counselor for disclosure decisions.

Frequently Asked Questions

1. Does a Factor V Leiden result mean I will get a blood clot? No. It is a risk factor, not a diagnosis. Most heterozygous carriers never have a clot. Your absolute annual risk stays low — roughly 4-5 per 1,000 carriers per year versus about 1 per 1,000 in non-carriers.

2. Will my children inherit it? Each child of a single heterozygous parent has about a 50% chance of inheriting one copy. Inheriting the variant is not the same as developing a clot. A genetic counselor (nsgc.org) can explain the pattern for your family.

3. Will this affect my health or life insurance? In the US, GINA blocks health insurers and employers from using genetic data — but it does not cover life, disability, or long-term-care insurance. Canada’s 2017 law is broader. Consider this before diagnostic testing.

4. Can my employer find out? Under GINA, US employers cannot use your genetic information to make employment decisions. Canada’s Genetic Non-Discrimination Act adds further protection. Still, discuss privacy concerns with a genetic counselor before testing.

5. Should I get a second opinion or see a specialist? For “variant detected” with no symptoms, your primary care physician is usually enough. See a hematologist or genetic counselor if you have a personal or strong family clot history, a homozygous result, or are planning pregnancy. Find one at nsgc.org.

6. Do I need to take blood thinners for the rest of my life? Almost certainly not, if you have never had a clot. There is no evidence supporting routine lifelong anticoagulation for asymptomatic carriers. Even after a clot, treatment duration depends on whether it was provoked and on bleeding risk — not on carrier status alone.

7. Is it safe for me to fly long distances or take birth control? Long flights are fine with sensible precautions: stay hydrated, move, and flex your calves. Estrogen-containing birth control raises clot risk and compounds it in carriers, so discuss non-estrogen options with your clinician before deciding.

Summary

Factor V Leiden is the most common inherited thrombophilia in people of European ancestry, present in about 3-8% of them. A DTC “variant detected” result can feel like a diagnosis, but the research tells a calmer story. The variant weakens one clotting brake, raising relative clot risk 3-8x for carriers — yet the absolute risk stays low, and most carriers never have a clot.

Professional societies have converged on a reassuring, evidence-based stance. Routine thrombophilia screening of asymptomatic people is not recommended. Carrier status alone does not require lifelong blood thinners. And DOACs — not warfarin — are now first-line if a clot does occur. Prevention is about managing high-risk windows, not taking a daily pill. And before diagnostic testing, understand GINA’s life-insurance gap and Canada’s stronger law. For the decisions that genuinely need judgment — homozygosity, pregnancy, or multiple risk factors — a genetic counselor (nsgc.org) or physician is the right partner, not a search engine.

This article is for educational purposes only. It is not a substitute for advice from a licensed physician, board-certified medical geneticist, or board-certified genetic counselor. For any decisions about testing, treatment, or care, consult a qualified clinician. In emergencies, call 911.

References

1. Bertina RM et al. (1994). Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. https://pubmed.ncbi.nlm.nih.gov/8164741/
2. MedlinePlus Genetics / NIH National Library of Medicine. Factor V Leiden thrombophilia. https://medlineplus.gov/genetics/condition/factor-v-leiden-thrombophilia/
3. CDC — Division of Blood Disorders. Venous Thromboembolism (Blood Clots) — Inherited Thrombophilia / Factor V Leiden. https://www.cdc.gov/blood-clots/about/index.html
4. Blom JW, Doggen CJM, Osanto S, Rosendaal FR — MEGA study (2005). Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. https://pubmed.ncbi.nlm.nih.gov/15701912/
5. Folsom AR, Cushman M et al. — LITE cohort (2002). Prospective study of the factor V Leiden mutation and incident venous thromboembolism. American Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/11897096/
6. Rosendaal FR (1999). Venous thrombosis: a multicausal disease. Lancet. https://pubmed.ncbi.nlm.nih.gov/10227233/
7. Middeldorp S, Henkens CMA et al. (1998). The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Annals of Internal Medicine. https://pubmed.ncbi.nlm.nih.gov/9669967/
8. Ortel TL, Neumann I et al. — American Society of Hematology (2020). ASH 2020 guidelines for management of venous thromboembolism: treatment of DVT and PE. Blood Advances. https://pubmed.ncbi.nlm.nih.gov/33007077/
9. Stevens SM, Woller SC et al. — ACCP / CHEST (2021). Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline. Chest. https://pubmed.ncbi.nlm.nih.gov/34352278/
10. Middeldorp S et al. — American Society of Hematology (2023). ASH 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Advances. https://pubmed.ncbi.nlm.nih.gov/37195076/
11. U.S. Food and Drug Administration — Drug Approval Records; Health Canada. Approvals of direct oral anticoagulants (rivaroxaban, apixaban, dabigatran, edoxaban). https://www.accessdata.fda.gov/scripts/cder/daf/
12. U.S. EEOC — Genetic Information Nondiscrimination Act of 2008; Government of Canada — Genetic Non-Discrimination Act (S.C. 2017, c. 3). https://www.eeoc.gov/genetic-information-discrimination
13. Kujovich JL — GeneReviews (NCBI Bookshelf, University of Washington). Factor V Leiden Thrombophilia. https://www.ncbi.nlm.nih.gov/books/NBK1368/

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Last updated: 2026-07-19

Author: Yu Mizuno (Editor-in-Chief, non-physician), GeneLumen editorial team. This article aggregates 13 sources from peer-reviewed medical literature and public health agencies (tier 1=A / tier 2=B), including NIH/MedlinePlus, the CDC, the FDA and Health Canada, the American Society of Hematology (ASH), the ACCP/CHEST guideline panel, GeneReviews, and PubMed-indexed publications.

This article is for educational purposes only and is not a substitute for medical advice from a licensed physician, board-certified medical geneticist, or board-certified genetic counselor. In emergencies, call 911 (US/Canada) or 119 (Japan).

Related: Genetic Diseases category

🇯🇵 For readers in Japan — a separate Japanese edition written for Japan’s healthcare system (not a translation): https://genelumen.com/ja/ja-metabolic-hematologic-genetic/factor-v-leiden-inheritance-thrombosis-risk