Gene:
F5
coagulation factor V (proaccelerin, labile factor)

last updated 02/07/2014

1. DPWG Guideline for hormonal contraceptives for systemic use and F5

Summary

In individuals who carry the Factor V Leiden allele and have a family history of thrombotic events, estrogen-containing oral contraceptives should be avoided and alternative forms of contraception used.

Annotation

The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for hormonal contraceptives for systemic use based on Factor V Leiden (FVL, or F5) genotype [Article:21412232]. They suggest that in individuals who carry the Factor V Leiden allele and have a family history of thrombotic events, estrogen-containing oral contraceptives should be avoided and alternative forms of contraception used.

Phenotype (Genotype) Therapeutic Dose Recommendation Level of Evidence Clinical Relevance
F5 homozygous rs6025 TT Positive (family) history of thrombotic events: avoid estrogen-containing oral contraceptives and select alternative (e.g., copper intrauterine device, progestin-only contraceptive). Negative (family) history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10 9/l; leucopenia 1.0-2.0x10 9/l; thrombocytopenia 25-50x10 9/l; severe diarrhea
F5 heterozygous rs6025 CT Positive (family) history of thrombotic events: avoid estrogen-containing oral contraceptives and select alternative (e.g., copper intrauterine device, progestin-only contraceptive). Negative (family) history of thrombotic events: avoid additional risk factors (e.g., obesity, smoking). Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10 9/l; leucopenia 1.0-2.0x10 9/l; thrombocytopenia 25-50x10 9/l; severe diarrhea
  • *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
  • S: statistically significant difference.

PharmGKB annotates drug labels containing pharmacogenetic information approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency, Japan (PMDA), and Health Canada (Santé Canada) (HCSC). PharmGKB annotations provide a brief summary of the PGx in the label, an excerpt from the label and a downloadable highlighted label PDF file. A list of genes and phenotypes found within the label is mapped to label section headers and listed at the end of each annotation. PharmGKB also attempts to interpret the level of action implied in each label with the "PGx Level" tag.

See the legend for more information about drug label sources and PGx Levels.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA, PMDA, HCSC or other Medicine Agencies around the world - please contact feedback.


Annotated Labels

  1. FDA Label for eltrombopag and F5,SERPINC1
  2. FDA Label for tamoxifen and ESR1,ESR2,F2,F5
  3. EMA Label for eltrombopag and F5,SERPINC1
  4. EMA Label for ethinyl estradiol,norelgestromin and F5
  5. HCSC Label for eltrombopag and F5,SERPINC1
  6. HCSC Label for drospirenone,ethinyl estradiol and F5,PROC,PROS1,SERPINC1
  7. HCSC Label for ethinyl estradiol,norelgestromin and F2,F5,MTHFR,PROC,PROS1,SERPINC1

last updated 10/25/2013

1. FDA Label for eltrombopag and F5,SERPINC1

Actionable PGx

Summary

The FDA-approved drug label for eltrombopag (PROMACTA) notes that patients taking the drug have an increased risk of thromboembolism if they have antithrombin III deficiency (SERPINC1) or Factor V Leiden (F5).

There's more of this label. Read more.



last updated 10/25/2013

3. EMA Label for eltrombopag and F5,SERPINC1

Actionable PGx

Summary

The EMA European Public Assessment Report (EPAR) highlights that caution should be taken when administering eltrombopag in patients with known risk factors for thromboembolism, including Factor V Leiden (F5 gene) and ATIII deficiency (SERPINC1 gene).

There's more of this label. Read more.


last updated 05/08/2014

4. EMA Label for ethinyl estradiol,norelgestromin and F5

Genetic testing required

Summary

The EMA European Public Assessment Report (EPAR) for norelgestromin and ethinyl estradiol (Evra) contains information regarding its contraindication in women with known predisposition to venous thromboembolism (including Factor V Leiden, rs6025).

There's more of this label. Read more.


last updated 06/08/2015

5. HCSC Label for eltrombopag and F5,SERPINC1

Actionable PGx

Summary

The product monograph for eltrombopag (REVOLADE) states that caution should be used when administering the drug to patients with risk factors for thromboembolism, such as Factor V Leiden mutation (rs6025 in F5) and antithrombin III deficiency (SERPINC1).

There's more of this label. Read more.


last updated 06/08/2015

6. HCSC Label for drospirenone,ethinyl estradiol and F5,PROC,PROS1,SERPINC1

Actionable PGx

Summary

The product monograph for drospirenone and ethinyl estradiol (YAZ) states that the drug is contraindicated in women with Factor V Leiden mutation, antithrombin-III-deficiency, protein C deficiency and protein S deficiency (among other contraindications), due to the risk for arterial or venous thrombosis.

There's more of this label. Read more.


last updated 06/08/2015

7. HCSC Label for ethinyl estradiol,norelgestromin and F2,F5,MTHFR,PROC,PROS1,SERPINC1

Actionable PGx

Summary

The product monograph for norelgestromin and ethinyl estradiol (EVRA) states that the drug is contraindicated in women with Factor V Leiden mutation, antithrombin-III-deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinaemia due to mutations in the MTHFR gene and prothrombin mutation G20210A (among other contraindications), due to the risk for arterial or venous thrombosis.

There's more of this label. Read more.


PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

List of all variant annotations for F5

Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No Clinical Annotations available VA
rs6018 169511878T>G, 21000520T>G, 2450A>C, 48892A>C, Asn817Thr
T > G
Missense
Asn817Thr
rs6025 1601G>A, 1601G>G, 169519049T>C, 169519049T>T, 21007691T>C, 21007691T>T, 41721G>A, 41721G>G, Arg534=, Arg534Gln, F5:Factor V Leiden
T > C
Missense
Arg534Gln
No VIP available No Clinical Annotations available VA
rs7542281 169536439C>T, 21025081C>T, 24331G>A, 373+5020G>A
C > T
Intronic
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Alternate Names:  None
Alternate Symbols:  None
PharmGKB Accession Id: PA159

Details

Cytogenetic Location: chr1 : q24.2 - q24.2
GP mRNA Boundary: chr1 : 169481192 - 169555769
GP Gene Boundary: chr1 : 169478192 - 169565769
Strand: minus

Visualization

UCSC has a Genome Browser that you can use to view PharmGKB annotations for this gene in context with many other sources of information.

View on UCSC Browser
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

Factor V is an essential coagulation cofactor that enhances thrombin activation by factor Xa. In 1987, Jenny et al. determined the primary structure of the factor V gene, F5, by cloning from a human fetal liver cDNA library. Riddell et al. and Wang et al. mapped the gene to chromosome 1q23. F5 is 72,313 bp with a 6,672 bp coding region consisting of 25 exons. Factor V is a 330 kDa single chain glycoprotein comprised of 2,224 amino acid residues. [Article:3220473, 3110773, 11950687, 7989361, 2827731]

A total of 433 validated polymorphisms are described in the dbSNP database; 40 of these are in the coding region and 22 result in an amino acid change. Based on SeattleSNPsdata, 181 SNPs have an allele frequency greater than 5% and of the 31 common coding polymorphisms, 18 are nonsynonymous. The most commonly studied variant in F5 is the 1691G>A substitution (Arg506Gln; the nucleotide position relative to start of sequence for F5 published by Jenny et al. PMID:3110773, which is also known as Factor V Leiden (FVL). FVL prevents deactivation of coagulation factor V by activated protein C. [Article:8164741]

Venous thromboembolism (VTE) is the most well-studied phenotype associated with FVL. The risk of VTE is greater among individuals with FVL, particularly among smokers and women using oral contraceptives or estrogen hormone replacement therapy. The relationship with arterial thrombosis is less clear. FVL has also been implicated as a risk factor for small bowel infarction, mortality in sepsis, restensosis, Budd-Chiari syndrome, obstetric complications such as VTE, preeclampsia, abruptio placentae, fetal growth retardation, and late fetal loss, ischemic stroke and porencephaly. Numerous variations in F5 have been associated with states of thrombophilia or parahemophilia, however few have been extensively studied. [Article:16113779, 14574075, 16651467, 11859850, 12069454, 7877648, 9207293, 9245936, 9878639, 10666427, 11435304, 12070000, 16606808, 15534175, 14660985, 15118525]

Citation
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
History

Submitted by Jennifer Bushwitz, Michael A. Pacanowski, Julie A. Johnson (PEAR)

Variant Summaries rs6025
Drugs
Diseases

Appendix

Gene Common Name coagulation factor V, proaccelerin, labile factor

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

PharmGKB contains no curated pathways for this gene. If you would like to volunteer to work on a pathway, please let us know.

External Pathways

Links to non-PharmGKB pathways.

  1. Common Pathway - (Reactome via Pathway Interaction Database)
  2. Exocytosis of Alpha granule - (Reactome via Pathway Interaction Database)
  3. extrinsic prothrombin activation pathway - (BioCarta via Pathway Interaction Database)
  4. intrinsic prothrombin activation pathway - (BioCarta via Pathway Interaction Database)
No related genes are available

Curated Information ?

Curated Information ?

Publications related to F5: 16

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
A pharmacogenetics-based warfarin maintenance dosing algorithm from northern chinese patients. PloS one. 2014. Chen Jinxing, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomic Association of Nonsynonymous SNPs in SIGLEC12, A1BG, and the Selectin Region and Cardiovascular Outcomes. Hypertension. 2013. McDonough Caitrin W, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration. Pharmacogenomics. 2012. Agosta Elisa, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics: From Bench to Byte- An Update of Guidelines. Clinical pharmacology and therapeutics. 2011. Swen J J, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Genetic and environmental factors determining clinical outcomes and cost of warfarin therapy: a prospective study. Pharmacogenetics and genomics. 2009. Jorgensen Andrea L, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13 ) on the effectiveness of statins: the GenHAT study. Pharmacogenetics and genomics. 2009. Maitland-van der Zee Anke-Hilse, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Predictive role of coagulation-balance gene polymorphisms in the efficacy of photodynamic therapy with verteporfin for classic choroidal neovascularization secondary to age-related macular degeneration. Pharmacogenetics and genomics. 2007. Parmeggiani Francesco, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Oral contraceptive use, thrombophilia and their interaction in young women with ischemic stroke. Haematologica. 2006. Martinelli Ida, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. Journal of thrombosis and haemostasis : JTH. 2005. Slooter A J C, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Venous thromboembolic disease in users of low-estrogen combined estrogen-progestin oral contraceptives. Contraception. 2004. Sidney Stephen, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Effect of factor V Leiden polymorphism in severe sepsis and on treatment with recombinant human activated protein C. Critical care medicine. 2004. Yan S Betty, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use. European heart journal. 2002. Legnani C, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Interaction of fibrinolysis and prothrombotic risk factors in neonates, infants and children with and without thromboembolism and underlying cardiac disease. a prospective study. Thrombosis research. 2001. Nowak-Göttl U, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 1999. Martinelli I, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. British journal of haematology. 1996. Rintelen C, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994. Vandenbroucke J P, et al. PubMed

LinkOuts

NCBI Gene:
2153
OMIM:
188055
227400
600880
601367
612309
UCSC Genome Browser:
NM_000130
RefSeq RNA:
NM_000130
RefSeq Protein:
NP_000121
RefSeq DNA:
NG_011806
NT_004487
UniProtKB:
FA5_HUMAN (P12259)
Ensembl:
ENSG00000198734
GenAtlas:
F5
GeneCard:
F5
MutDB:
F5
ALFRED:
LO000606M
HuGE:
F5
Comparative Toxicogenomics Database:
2153
ModBase:
P12259
HGNC:
3542

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