Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released Status (Pediatric): Incomplete (Consensus scoring is Incomplete) P

Condition: Factor V Leiden, Heterozygous
Mode(s) of Inheritance: Autosomal Dominant
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
F50008560 (thrombophilia due to activated protein c resistance)
Limited Actionability
Actionability Rationale
All experts disagreed with the moderate assertion computed according to the rubric. A limited assertion was agreed upon to reflect the limited actionability based on genotype alone for individuals who are heterozygous. Based on practice guidance asymptomatic screening for this genetic finding is currently not recommended.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: F5 0008560 (OMIM:188055)
VTE / Assessment for VTE risk factors
Not Scored
VTE / Avoid estrogen-containing compounds that exacerbate VTE risk
VTE / Pharmacological prophylaxis

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Venous thromboembolism (VTE) was estimated to occur at an annual rate of 117 per 100,000 per year in U.S. and European populations; the estimate for deep vein thrombosis (DVT) was 48-66 per 100,000 and for pulmonary embolism (PE) was 33-69 per 100,000. A factor V Leiden (FVL) mutation is present in 15-20% of individuals with an initial episode of VTE.
Clinical Features
(Signs / symptoms)
Factor V Leiden refers to a single base change in the F5 gene (G1691A) that eliminates 1 of its 3 activated protein C cleavage sites. Consequently, factor V is inactivated at a lower rate, leading to more thrombin generation and enhanced potential for clot formation. FVL is associated with an increased risk for DVT and PE, collectively referred to as venous thromboembolism. FVL is the most common known heritable risk factor for thrombosis.
2 1 3
Natural History
(Important subgroups & survival / recovery)
VTE contributes to an estimated 60,000 to 100,000 deaths annually. DVT of the lower extremities is the most frequent manifestation of VTE; clot formation in the venous sinuses results in cerebral venous thrombosis (CVT), a type of stroke. The most common life-threatening manifestation of DVT is the subsequent development of PE, resulting in an 18-fold higher risk of early death compared to patients with DVT alone. In one study, DVT survival at 1 week was 93% whereas PE survival at 1 week was 71%. VTE recurs frequently, most often in the first 6 months to a year after the first event, but the hazard recurrence rate never drops to zero after that, suggesting that VTE is a chronic disease with episodic recurrence. Approximately 30% of patients with DVT develop post-thrombotic leg syndrome, characterized by chronic leg pain, swelling, dermatitis, and ulcers. It is more likely to occur after recurrent episodes of DVT.
VTE incidence may be higher in African American populations and lower in Asian, Asian American, and Native American populations. VTE increases with age, with marked increases after age 60. Incidence rates are somewhat higher in women during childbearing years compared to men, but higher in men after age 45. Independent predictors of VTE risk include prior VTE, family history of VTE, malignancy, major surgery, trauma, hospitalization, nursing home residency, and obesity. In women, risk of VTE is also increased during and shortly after pregnancy, and with use of combined (estrogen-containing) oral contraceptives or hormone replacement therapy. FVL interacts with clinical risk factors to compound the risk of incident VTE. For example, FVL in the heterozygous state increases the pre-existing risk of VTE in pregnancy, and of CVT in women who use oral contraceptives. The effect of FVL on VTE risk is heightened in those with a personal or family history of VTE. However, studies indicate that heterozygosity for FVL is not associated with an increase in mortality or reduction in normal life expectancy.
2 1 4 3 5
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
Recommendations and/or evidence regarding patients heterozygous for FVL were found for the following clinical scenarios of additional thrombotic risk:
Treatment of idiopathic venous thromboembolism or cerebral thromboembolism
Among 13 studies in a systematic review, the pooled OR for recurrent thrombosis was 1.56 (95% CI, 1.14-2.12) for individuals heterozygous for FVL compared with patients without the mutation. However, when analyses were limited to 6 studies reporting only individuals with idiopathic VTE, the pooled OR for recurrent thrombosis was 1.17 (95% CI, 0.63-2.18) for those with heterozygous FVL relative to individuals without. Studies demonstrate that pharmacological prophylaxis (usually low molecular weight heparin [LMWH] or warfarin, as appropriate) reduces recurrent events in patients with FVL; however, the magnitude of this relative reduction is comparable with that seen in individuals without mutations. This suggests that other nongenetic factors may be as important in determining the risk of recurrence and the absolute magnitude of benefit conferred by anticoagulation. (Tier 1)
VTE in Pregnancy
Heterozygous FVL carriers with no personal or family VTE history, or other thrombotic risk factors require no change in antepartum or postpartum management compared to those without heritable thrombophilia. The addition of heterozygous FVL status to other existing thrombotic risk factors, including a personal or family history of VTE, may warrant antepartum and/or postpartum pharmacological prophylaxis. (Tier 2)
7 8 9
Pregnant women with no personal or family history of VTE and who are heterozygous for FVL have been reported to have a VTE risk of approximately 0.5 to 1.2%, although the true risk is not well defined. Pregnant women who do not carry FVL have a VTE risk that may be about 8-fold lower. Pregnant women heterozygous for FVL and with a personal VTE history have a risk of recurrence during pregnancy that may be as high as 10 to 20%. (Tier 3)
10 8 9
The effects of antenatal plus postpartum low molecular weight heparin prophylaxis vs none were estimated from indirect evidence of pharmacological prophylaxis in patients undergoing hip arthroplasty:
•FVL Heterozygotes with VTE family history: 10 (12 to 5) fewer VTE compared to baseline 15 VTE per 1000
•No significant difference in antepartum or postpartum bleeding events (baseline antepartum risk of major bleeding events from a systematic review of the safety and efficacy of pharmacological prophylaxis during pregnancy). (Tier 1)
After cesarean section, women known to have inherited thrombophilia should be considered for pharmacological prophylaxis following delivery. Indirect evidence of VTE events from patients undergoing general surgery and treated with LMWH vs. placebo suggests prophylaxis for women at high risk (defined as absolute VTE risk of more than 3%), including women heterozygous for FVL.
•High risk women undergoing cesarean section and given prophylaxis: 21 fewer VTEs per 1000 compared to those not given pharmacological prophylaxis (baseline 40 VTE per 1000).
•Twenty more bleeding events per 1000 compared to a baseline of 20 events per 1000 in those not treated (baseline risk estimate from a decision model evaluating the risks and benefits of post-cesarean pharmacological prophylaxis). (Tier 1)
Pregnancy loss
For women with inherited thrombophilia and a history of pregnancy complications including pregnancy loss, it is suggested not to use pharmacological prophylaxis. (Tier 1)
Two meta-analyses of poorly documented case-control and/or cohort studies report that the odds of pregnancy loss in women with FVL was higher as compared with women without FVL; OR=1.52 (95% CI, 1.06-2.19) and OR=2.03 (95% CI: 1.29-3.17). Two randomized trials found no difference in loss rates in women (few FVL carriers) with recurrent pregnancy loss among groups treated with LMWH plus aspirin, aspirin only, or placebo. Meta-analyses have also reported insufficient evidence that these treatments reduce loss rates in women with recurrent pregnancy loss who do not have antiphospholipid syndrome. No specific trials of pharmacological prophylaxis in FVL carriers were cited. (Tier 1)
Screening when FVL status is unknown
There is adequate evidence to recommend against routine testing for FVL in adults with VTE given testing does not influence the initial management of VTE (see " Treatment of idiopathic venous thromboembolism or cerebral thromboembolism." (Tier 1)
10 8 1 12
Routine screening of all women for FVL and other thrombophilias before initiating combination contraception is not recommended. Despite the increased relative risk, the absolute population risk is low because of the low prevalence of this and other thrombophilias and of VTE. In general, screening for thrombophilia is not recommended except in case of personal history of unprovoked VTE or a first-degree relative with a history of high-risk thrombophilia. (Tier 2)
8 12
Routine laboratory screening for heritable thrombophilias prior to additional risk situations such as hormone replacement therapy, pregnancy, or elective major surgery is not recommended. (Tier 2)
No surveillance recommendations have been provided for the Adult context.
Circumstances to Avoid
Alternative methods of postpartum contraceptive options should be considered instead of estrogen-containing (combined) oral contraceptives for women known to carry FVL. In one study the annual risk of venous thromboembolism was 5.7 per 10,000 among FVL carriers, compared with 28.5 per 10,000 among FVL heterozygous women using estrogen-containing contraceptives. (Tier 2)
In another study the OR for ischemic stroke was 11.2 (95% CI, 4.2-29) for women using oral contraceptives who were heterozygous for FVL compared to non-users without an FVL allele. Non-FVL carriers who used oral contraceptives had an OR of 2.6 (95% CI, 1.7-4.0) for ischemic stroke compared to non-users. (Tier 5)
Hormone replacement therapy
Women with an FVL allele and a history of VTE should avoid HRT. Asymptomatic women who are heterozygous for FVL should be counseled on the risks of HRT use and should be encouraged to consider alternative control of menopausal symptoms. Women found to be FVL heterozygotes and who used hormone replacement therapy had a 7 to 15-fold higher thrombotic risk than non-users without the mutation. (General population HRT users have a 2 to 4-fold increased risk of VTE compared to non-users.) Some evidence suggests that the thrombotic risk from transdermal HRT is lower than the thrombotic risk from oral preparations, in women with and without prothrombotic mutations. However, there are no prospective trials confirming the safety in women with thrombophilia. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Dominant
Prevalence of Genetic Variants
In the United States, approximately 5.1%, 2.0%, and 1.2% of the non-Hispanic white, Hispanic white, and African American populations are heterozygous for the FVL mutation, respectively. (Tier 3)
(Include any high risk racial or ethnic subgroups)
Lifetime risk for thrombosis in a heterozygote is approximately 10%. FVL heterozygotes identified from general population screening had an absolute incidence of VTE of approximately 2 VTE events per 1000 persons per year. (Tier 3)
Information on the penetrance of variants was not available for the Adult context.
Relative Risk
(Include any high risk racial or ethnic subgroups)
In a systematic review of observational studies of relatives of FVL probands, the pooled relative risk of VTE for FVL carriers was 3.69 (95% CI, 2.27-6.00) in four retrospective studies. Another systematic review with slightly different inclusion criteria reported that the pooled OR for VTE in relatives with heterozygosity for FVL compared with relatives without the mutation was 3.5 (95% CI, 2.5-5.0) in seven observational studies. Finally, in a systematic review of case-control studies, the pooled OR of FVL for VTE was 4.9 (95% CI, 4.4- 5.5). (Tier 1)
14 15 6
Although a FVL allele is an established risk factor, it does not predict thrombosis with certainty because the clinical course is variable, even within the same family. (Tier 4)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions include pharmacological prophylaxis (usually low molecular weight heparin [LMWH] or warfarin, as appropriate), as well as avoidance of certain types of medications. Pharmacological prophylaxis carries a risk of bleeding; risks and benefits of pharmacological prophylaxis must be balanced against the risk of VTE. A systematic review of studies using LMWH during and/or immediately following pregnancy reported an overall frequency of significant bleeding of 1.98% (95% CI, 1.50%-2.57%). Bleeding rates while on warfarin treatment for VTE are approximately 1%.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Routine laboratory screening for heritable thrombophilias is not recommended. This includes testing prior to risk situations such as prescription of oral contraceptives or hormone replacement therapy, pregnancy, elective major surgery or central venous catheter insertion. Because testing for FVL does not influence initial management of VTE, routine testing in this situation is also not recommended. (Tier 1)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genet Med. (2011) 13(1):67-76.
2. Prevention of deep vein thrombosis and pulmonary embolism. Publisher: American College of Obstetricians and Gynecologists (ACOG). (2012) Website:
3. JL Kujovich. Factor V Leiden Thrombophilia. 1999 May 14 [Updated 2010 Mar 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:
4. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. (2015) 12(8):464-74.
5. Press RD, Bauer KA, Kujovich JL, Heit JA. Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Pathol Lab Med. (2002) 126(11):1304-18.
6. Segal JB, Brotman DJ, Necochea AJ, Emadi A, Samal L, Wilson LM, Crim MT, Bass EB. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA. (2009) 301(23):2472-85.
7. Reducing the Risk of Venous Thromboembolism during Pregnancy and the Puerperium. Publisher: Royal College of Obstetricians and Gynaecologists (RCOG). (2015) Website:
8. ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet Gynecol. (2013) 122(3):706-17.
9. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. (2012) 141(2 Suppl):e691S-736S.
10. Prevention and management of venous thromboembolism. A national clinical guideline. Publisher: Scottish Intercollegiate Guidelines Network (SIGN). (2015) Website:
11. Bradley LA, Palomaki GE, Bienstock J, Varga E, Scott JA. Can Factor V Leiden and prothrombin G20210A testing in women with recurrent pregnancy loss result in improved pregnancy outcomes?: Results from a targeted evidence-based review. Genet Med. (2012) 14(1):39-50.
12. Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL, Howard VJ, Lichtman JH, Lisabeth LD, Pina IL, Reeves MJ, Rexrode KM, Saposnik G, Singh V, Towfighi A, Vaccarino V, Walters MR. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. (2014) 45(5):1545-88.
13. Slooter AJ, Rosendaal FR, Tanis BC, Kemmeren JM, van der Graaf Y, Algra A. Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. J Thromb Haemost. (2005) 3(6):1213-7.
14. Gohil R, Peck G, Sharma P. The genetics of venous thromboembolism. A meta-analysis involving approximately 120,000 cases and 180,000 controls. Thromb Haemost. (2009) 102(2):360-70.
15. Langlois NJ, Wells PS. Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review. Thromb Haemost. (2003) 90(1):17-26.
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