Factor V Leiden

Factor V Leiden (rs6025 or F5 p.R506Q[1]) is a variant (mutated form) of human factor V (one of several substances that helps blood clot), which causes an increase in blood clotting (hypercoagulability). Due to this mutation, Protein C, an anticoagulant protein which normally inhibits the pro-clotting activity of factor V, is not able to bind normally to Factor V, leading to a hypercoagulable state, i.e., an increased tendency for the patient to form abnormal and potentially harmful blood clots.[2] Factor V Leiden is the most common hereditary hypercoagulability (prone to clotting) disorder amongst ethnic Europeans.[3][4][5] It is named after the Dutch city Leiden, where it was first identified in 1994 by Prof R. Bertina under the direction of (and in the laboratory of) Prof P. Reitsma.[6] Despite the increased risk of VTE, people with one copy of this gene have not been found to have shorter lives than the general population.[7]

Factor V Leiden thrombophilia
SpecialtyHematology

Signs and symptoms

Abnormal, recurrent venous thromboses.

Pathophysiology

In the normal person, factor V functions as a cofactor to allow factor Xa to activate prothrombin, resulting in the enzyme thrombin. Thrombin in turn cleaves fibrinogen to form fibrin, which polymerizes to form the dense meshwork that makes up the majority of a clot. Activated protein C (aPC) is a natural anticoagulant that acts to limit the extent of clotting by cleaving and degrading factor V.

SNP: Factor V Leiden
Name(s)Factor V Leiden, Arg506Gln, R506Q, G1691A
GeneFactor V
Chromosome1
External databases
EnsemblHuman SNPView
dbSNP6025
HapMap6025
SNPedia6025
ALFREDSI001216K

Factor V Leiden is an autosomal dominant genetic condition that exhibits incomplete penetrance, i.e. not every person who has the mutation develops the disease. The condition results in a factor V variant that cannot be as easily degraded by aPC (activated Protein C). The gene that codes the protein is referred to as F5. Mutation of this gene—a single nucleotide polymorphism (SNP) is located in exon 10.[8] As a missense substitution of amino acid R to amino acid Q, it changes the protein's amino acid from arginine to glutamine. Depending on the chosen start the position of the nucleotide variant is either at position 1691 or 1746.[9] It also affects the amino acid position for the variant, which is either 506 or 534. (Together with the general lack of nomenclature standard, this variance means that the SNP can be referred to in several ways, such as G1691A, c.1691G>A, 1691G>A, c.1746G>A, p.Arg534Gln, Arg506Gln, R506Q or rs6025.) Since this amino acid is normally the cleavage site for aPC, the mutation prevents efficient inactivation of factor V. When factor V remains active, it facilitates overproduction of thrombin leading to generation of excess fibrin and excess clotting.

The excessive clotting that occurs in this disorder is almost always restricted to the veins, where the clotting may cause a deep vein thrombosis (DVT). If the venous clots break off, these clots can travel through the right side of the heart to the lung where they block a pulmonary blood vessel and cause a pulmonary embolism. It is extremely rare for this disorder to cause the formation of clots in arteries that can lead to stroke or heart attack, though a "mini-stroke", known as a transient ischemic attack, is more common. Given that this disease displays incomplete dominance, those who are homozygous for the mutated allele are at a heightened risk for the events detailed above versus those who are heterozygous for the mutation.

Diagnosis

Suspicion of factor V Leiden being the cause for any thrombotic event should be considered in any Caucasian patient below the age of 45, or in any person with a family history of venous thrombosis.There are a few different methods by which this condition can be diagnosed. Most laboratories screen 'at risk' patients with either a snake venom (e.g. dilute Russell's viper venom time) based test or an aPTT based test. In both methods, the time it takes for blood to clot is decreased in the presence of the factor V Leiden mutation. This is done by running two tests simultaneously; one test is run in the presence of activated protein C (APC) and the other, in the absence. A ratio is determined based on the two tests and the results signify to the laboratory whether APC is working or not.There is also a genetic test that can be done for this disorder. The mutation (a 1691G→A substitution) removes a cleavage site of the restriction endonuclease MnlI, so PCR, treatment with MnlI, and then DNA electrophoresis will give a diagnosis. Other PCR based assays such as iPLEX can also identify zygosity and frequency of the variant.

Management

As there is no cure yet, treatment is focused on prevention of thrombotic complications. Anticoagulants are not routinely recommended for people with factor V Leiden, unless there are additional risk factors present, but are given when such an event occurs.[10][11] A single occurrence of deep vein thrombosis or pulmonary embolism in people with Factor V Leiden warrants temporary anticoagulant treatment, but generally not lifelong treatment.[10] In addition, temporary treatment with an anticoagulant such as Heparin may be required during periods of particularly high risk of thrombosis, such as major surgery.[10]

Epidemiology

Studies have found that about 5 percent of Caucasians in North America have factor V Leiden. Data have indicated that prevalence of factor V Leiden is greater among Caucasians than minority Americans.[12][13] One study also suggested "that the factor V‐Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non‐European groups."[14]

Up to 30 percent of patients who present with deep vein thrombosis (DVT) or pulmonary embolism have this condition. The risk of developing a clot in a blood vessel depends on whether a person inherits one or two copies of the factor V Leiden mutation. Inheriting one copy of the mutation from a parent (heterozygous) increases by fourfold to eightfold the chance of developing a clot. People who inherit two copies of the mutation (homozygous), one from each parent, may have up to 80 times the usual risk of developing this type of blood clot.[15] Considering that the risk of developing an abnormal blood clot averages about 1 in 1,000 per year in the general population, the presence of one copy of the factor V Leiden mutation increases that risk to between 4 in 1,000 to 8 in 1,000. Having two copies of the mutation may raise the risk as high as 80 in 1,000. It is unclear whether these individuals are at increased risk for recurrent venous thrombosis. While only 1 percent of people with factor V Leiden have two copies of the defective gene, these homozygous individuals have a more severe clinical condition. The presence of acquired risk factors for venous thrombosis—including smoking, use of estrogen-containing (combined) forms of hormonal contraception, and recent surgery—further increase the chance that an individual with the factor V Leiden mutation will develop DVT.

Women with factor V Leiden have a substantially increased risk of clotting in pregnancy (and on estrogen-containing birth control pills or hormone replacement) in the form of deep vein thrombosis and pulmonary embolism. They also may have a small increased risk of preeclampsia, may have a small increased risk of low birth weight babies, may have a small increased risk of miscarriage and stillbirth due to either clotting in the placenta, umbilical cord, or the fetus (fetal clotting may depend on whether the baby has inherited the gene) or influences the clotting system may have on placental development.[16] Note that many of these women go through one or more pregnancies with no difficulties, while others may repeatedly have pregnancy complications, and still others may develop clots within weeks of becoming pregnant.

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See also

References
  1. Klarin D, Busenkell E, Judy R, Lynch J, Levin M, Haessler J, et al. (November 2019). "Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease" (PDF). Nature Genetics. 51 (11): 1574–1579. doi:10.1038/s41588-019-0519-3. PMC 6858581. PMID 31676865.
  2. De Stefano V, Leone G (1995). "Resistance to activated protein C due to mutated factor V as a novel cause of inherited thrombophilia". Haematologica. 80 (4): 344–56. PMID 7590506.
  3. Ridker PM, Miletich JP, Hennekens CH, Buring JE (1997). "Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening". JAMA. 277 (16): 1305–7. doi:10.1001/jama.277.16.1305. PMID 9109469.
  4. Gregg JP, Yamane AJ, Grody WW (December 1997). "Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations". American Journal of Medical Genetics. 73 (3): 334–6. doi:10.1002/(SICI)1096-8628(19971219)73:3<334::AID-AJMG20>3.0.CO;2-J. PMID 9415695.
  5. De Stefano V, Chiusolo P, Paciaroni K, Leone G (1998). "Epidemiology of factor V Leiden: clinical implications". Seminars in Thrombosis and Hemostasis. 24 (4): 367–79. doi:10.1055/s-2007-996025. PMID 9763354.
  6. Bertina RM, Koeleman BP, Koster T, et al. (May 1994). "Mutation in blood coagulation factor V associated with resistance to activated protein C". Nature. 369 (6475): 64–7. Bibcode:1994Natur.369...64B. doi:10.1038/369064a0. PMID 8164741. S2CID 4314040.
  7. Kujovich JL (January 2011). "Factor V Leiden thrombophilia". Genetics in Medicine. 13 (1): 1–16. doi:10.1097/GIM.0b013e3181faa0f2. PMID 21116184.
  8. "SNP linked to Gene F5". NCBI.
  9. Jennifer Bushwitz; Michael A. Pacanowski & Julie A. Johnson (2006-10-11). "Important Variant Information for F5". PharmGKB. Archived from the original on 2011-07-27. Retrieved 2008-09-10.
  10. Ornstein, Deborah L.; Cushman, Mary (2003). "Factor V Leiden". Circulation. 107 (15): e94-7. doi:10.1161/01.CIR.0000068167.08920.F1. ISSN 0009-7322. PMID 12707252.
  11. Keo, Hong H; Fahrni, Jennifer; Husmann, Marc; Gretener, Silvia B. (2015). "Assessing the risk of recurrent venous thromboembolism – a practical approach". Vascular Health and Risk Management. 11: 451–9. doi:10.2147/VHRM.S83718. ISSN 1178-2048. PMC 4544622. PMID 26316770.
  12. Ridker, et al. "Ethnic distribution of factor V Leiden in 4047 men and women". Supra.
  13. Gregg, et al. "Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations". Supra.
  14. Id.
  15. What do we know about heredity and factor V Leiden thrombophilia? http://www.genome.gov/15015167#Q5
  16. Rodger MA, Paidas M, McLintock C, et al. (August 2008). "Inherited thrombophilia and pregnancy complications revisited". Obstetrics and Gynecology. 112 (2 Pt 1): 320–24. doi:10.1097/AOG.0b013e31817e8acc. PMID 18669729.

Further reading
Classification
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