Factor V Leiden

Factor V Leiden thrombophilia
Classification and external resources
Specialty Hematology
ICD-10 D68.5
ICD-9-CM 289.81
DiseasesDB 154

Factor V Leiden thrombophilia[1] is a genetic disorder of blood clotting. Factor V Leiden is a variant (mutated form) of human factor V (one of several substances that helps blood clot) that causes an increase in blood clotting (hypercoagulability). With this mutation, the protein secreted that helps blood not clot is unable to do so, and therefore clotting is more likely.[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 et al.[6]

Pathophysiology

In the normal person, factor V functions as a cofactor to allow factor Xa to activate 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
Gene Factor V
Chromosome 1
External databases
Ensembl Human SNPView
dbSNP 6025
HapMap 6025
SNPedia 6025
HgenetInfoDB 6025
ALFRED SI001216K

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.[7] As a missense substitution of base G to base A, 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.[8] 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 that 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. These are quick, three-minute, automated tests that most hospital laboratories can easily perform.

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.

Epidemiology

Studies have found that about 5 percent of Caucasians in North America have factor V Leiden. The condition is less common in Latin Americans and African-Americans and is extremely rare in people of Asian descent.

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.[9] 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.[10] 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.

See also

References

  1. ↑ also known as Leiden Factor 5 (and sometimes factor VLeiden)
  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. doi:10.1038/369064a0. PMID 8164741.
  7. ↑ "SNP linked to Gene F5". NCBI.
  8. ↑ Jennifer Bushwitz, Michael A. Pacanowski, and Julie A. Johnson (2006-10-11). "Important Variant Information for F5". PharmGKB.
  9. ↑ What do we know about heredity and factor V Leiden thrombophilia? http://www.genome.gov/15015167#Q5
  10. ↑ 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

External links

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