Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Complete (Actionability curation complete.)

GENE/GENE PANEL: F5
Condition: Factor V Leiden, Homozygous (also includes compound heterozygous FVL + prothrombin G20210A)
GENEDISEASE PAIRS: F5188055
Topic
Narrative Description of Evidence
Ref
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.
1
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.
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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 increases the pre-existing risk of VTE in pregnancy, and of CVT in women who use oral contraceptives. Similarly, interactions between more than one genetic risk factor further increase the risk of incident VTE. The effect of FVL on VTE risk is heightened in the homozygous state or in the presence of other heritable thrombophilic factors (including the next most common heritable thrombophilia, heterozygous prothrombin G20210A mutation), and in those with a personal or family history of VTE.
1 2 4 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
Homozygosity (OR, 2.6; 95% CI, 1.2-6.0) for FVL in probands is predictive of recurrent VTE compared with individuals without FVL. Compound heterozygosity for FVL and prothrombin G20210A also predicts recurrent VTE (OR, 4.8; 95% CI, 0.5-46). Thus, moderate evidence supports that homozygosity for FVL and compound FVL-prothrombin G20210A heterozygosity is predictive of recurrent VTE among individuals who have had a prior VTE. Studies demonstrate that pharmacological prophylaxis (usually low molecular weight heparin [LMWH] or warfarin, as appropriate) reduces recurrent events in patients with FVL (not homozygous-specific; likely mostly heterozygous); 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)
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VTE in Pregnancy
 
Women who are homozygous for FVL (especially those who have a family history of VTE) should be referred to a local expert and considered for antenatal pharmacological prophylaxis. (Tier 1)
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The risk of pregnancy-related VTE in homozygous FVL carriers has been reported as 1.5 to 5% (and ~5% in compound heterozygotes for FVL and prothrombin G20210A) in unrelated individuals with no VTE history and 10 to 17% (95% CI, 6.3-25.8) in FVL homozygous individuals with personal or family history of VTE. (Tier 3)
8 9
Women who are homozygous for FVL should be considered for postpartum pharmacological prophylaxis for 6 weeks regardless of VTE personal or family history. (Tier 1)
7 8
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 Homozygotes with VTE family history: 47 (56 to 31) fewer VTE compared to baseline 70 VTE per 1000
 
• FVL Homozygotes: 13 (16 to 6) fewer VTE compared to baseline 20 VTE per 1000
 
• No significant difference in antepartum or postpartum bleeding events.
8
After cesarean section, for women at increased risk of VTE due to FVL homozygosity, extended postpartum pharmacological prophylaxis is suggested; the optimal duration is not established. Indirect evidence from randomized controlled trials in patients undergoing general surgery suggests prophylaxis for women with an absolute VTE risk of more than 3% would result in 21 fewer symptomatic VTEs per 1000 (baseline 40 VTE per 1000) with an additional 20 major bleeding events per 1000 (baseline 20 per 1000). (Tier 2)
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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)
8
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)
10
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)
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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)
9 11
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)
7
Surveillance
No surveillance recommendations have been provided.
 
Family Management
There is adequate evidence to recommend against FVL testing in asymptomatic adult family members of patients with VTE and an FVL mutation, for the purpose of considering primary pharmacological prophylaxis. There is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high. (Tier 1)
1
Do not routinely offer thrombophilia testing to first-degree relatives of people with a history of VTE except in rare circumstances where this testing could affect treatment options. (Tier 2)
3
Molecular genetic testing can establish the genetic status of asymptomatic at-risk family members; however, the indications for family testing are unresolved. Clarification of FVL allele status may be useful in at-risk relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age. In the absence of evidence that early diagnosis of FVL reduces morbidity or mortality, decisions regarding testing should be made on an individual basis. (Tier 4)
3
Circumstances to Avoid
Contraception
 
Alternative methods of postpartum contraceptive options should be considered instead of combined oral contraceptives for women known to carry FVL. (Tier 2)
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FVL homozygous women with or without prior VTE should avoid estrogen-containing contraception. (Tier 3)
3
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)
9
The risk for VTE is markedly increased in users of combined oral contraceptive who are compound heterozygous for FVL and prothrombin G20210A, with reported odds ratios ranging from 17 to 110 compared to oral contraceptive users without either mutation. No data on risk among FVL homozygous women was available. (Tier 5)
12
Hormone replacement therapy
 
FVL homozygous women with or without prior VTE should avoid estrogen-containing HRT. FVL heterozygotes who used hormone replacement therapy had a 7 to 15-fold higher thrombotic risk than non-users without the mutation. No data was found on homozygotes. 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)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
 
Prevalence of Genetic Mutations
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. Corresponding rates of homozygosity are much lower (65, 10, and 4 per 100,000 individuals, respectively). Individuals with both an FVL mutation and a prothrombin G20210A mutation occur at the rate of 22 per 100,000. (Tier 3)
1 6
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
VTE penetrance in Factor V Leiden homozygotes is incomplete; estimates have not been reported. FVL homozygotes identified from general population screening had an absolute incidence of approximately 15 VTE events/1000 persons/year. (NOTE: Lifetime risk for thrombosis in a heterozygote is approximately 10%.) (Tier 3)
3
Information on relative risk was not available. Meta-analyses report odds ratios for VTE in FVL homozygotes or compound heterozygotes although odds ratios may not estimate relative risk in this setting.
 
In a comprehensive meta-analysis, the pooled OR for risk of VTE in FVL homozygotes compared to controls without FVL was 9.45 (95% CI, 6.72-13.3, p<0.00001). (Tier 1)
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In another meta-analysis, relatives who were homozygous for FVL compared with family members without the mutation had a pooled OR for first VTE of 18 (95% CI, 7.8- 40). Similarly, in family members who were compound heterozygotes for FVL and prothrombin G20210A mutations, the pooled OR for first VTE was 6.7 (95% CI, 2.9-16) The pooled OR for recurrence in FVL homozygotes was 2.65 (95% CI, 1.18-5.97) and for FVL - prothrombin G20210A compound heterozygotes was 4.81 (95%CI, 0.50-46.3). (Tier 1)
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Expressivity
Although a factor V 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)
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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%.
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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. With respect to specific detection of FVL homozygotes, genetic evaluation may occur only in high-risk individuals with a history of recurrent VTE, especially at young age, or those with strong family history of VTE at young age. In a prospective study, the absolute ten-year risk for VTE among FVL homozygotes was 51% in smokers over age 60 with a BMI greater than 30 kg/m2, but only 3% in nonsmokers younger than age 40 years who were not overweight.
3

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
VTE / Assessment for VTE risk factors
2
2C
IN
Not Scored
IN
VTE / Avoid estrogen-containing compounds that exacerbate VTE risk
2
2C
2D
3
9CD
VTE / Pharmacological prophylaxis for pregnant women
2
2C
2B
2
8CB
VTE / Pharmacological prophylaxis for men and non-pregnant women
2
2C
0D
2
6CD
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
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.
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: https://www.guideline.gov/summaries/summary/11429
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; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1368
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. Prevention and management of venous thromboembolism. a national clinical guideline. Publisher: Scottish Intercollegiate Guidelines Network (SIGN). (2015) Website: http://www.sign.ac.uk/pdf/sign122.pdf
8. 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.
9. ACOG Practice Bulletin No. 138: inherited thrombophilias in pregnancy. Obstet Gynecol. (2013) 122(3):706-17.
10. 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.
11. 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.
12. Mohllajee AP, Curtis KM, Martins SL, Peterson HB. Does use of hormonal contraceptives among women with thrombogenic mutations increase their risk of venous thromboembolism? a systematic review. Contraception. (2006) 73(2):166-78.
13. 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.
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