Factor V Leiden

Factor V Leiden thrombophilia
Specialty	Hematology

Factor V Leiden(rs6025orF5p.R506Q) is a variant (mutated form) of humanfactor 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 that 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.Factor V Leiden is the most commonhereditaryhypercoagulability (prone to clotting)disorderamongst ethnic Europeans.It is named after the Dutch city ofLeiden,where it was first identified in 1994 by Rogier Maria Bertina under the direction of (and in the laboratory of) Pieter Hendrick Reitsma.Despite the increased risk ofvenous thromboembolisms,people with one copy of this gene have not been found to have shorter lives than the general population.It is anautosomaldominantgenetic disorderwith incompletepenetrance.

Signs and symptoms

The symptoms of factor V Leiden vary among individuals. There are some individuals who have the F5 gene and who never develop thrombosis, while others have recurring thrombosis before the age of 30 years. This variability is influenced by the number of F5 gene (chromosome 1) mutations a person has, the presence of other gene alterations related to blood clotting, and circumstantial risk factors, such as surgery, use of oral contraceptives and pregnancy.

Symptoms of factor V Leiden include:

• Having a firstDVT(deep vein thrombosis) orPE(pulmonary embolism) before age 50.
• Having recurring DVT or PE.
• Having venous thrombosis in unusual sites in the body such as the brain or the liver.
• Having a DVT or PE during or right after pregnancy.
• Having a history of unexplained pregnancy loss in the second or third trimester.
• Having a DVT or PE and a strong family history of venous thromboembolism.

The use of hormones, such as oral contraceptive pills (OCPs) and hormone replacement therapy (HRT), including estrogen and estrogen-like drugs taken after menopause, increases the risk of developing DVT and PE. Healthy women taking OCPs have a three- to four-fold increased risk of developing a DVT or PE compared with women who do not take OCP. Women with factor V Leiden who take OCPs have about a 35-fold increased risk of developing a DVT or PE compared with women without factor V Leiden and those who do not take OCPs. Likewise, postmenopausal women taking HRT have a two- to three-fold higher risk of developing a DVT or PE than women who do not take HRT, and women with factor V Leiden who take HRT have a 15-fold higher risk. Women with heterozygous factor V Leiden who are making decisions about OCP or HRT use should take these statistics into consideration when weighing the risks and benefits of treatment.

Pathophysiology

In the normal pathway, factor V functions as acofactorto allowfactor Xato activateprothrombin,resulting in theenzymethrombin.Thrombin in turn cleavesfibrinogento formfibrin,which polymerizes to form the dense meshwork that makes up the majority of aclot.Activatedprotein Cis a naturalanticoagulantthat acts to limit the extent of clotting by cleaving and degrading factor V.

SNP: rs6025
Name(s)	Factor V Leiden, Arg506Gln, R506Q, G1691A
Gene	Factor V
Chromosome	1
External databases
Ensembl	Human SNPView
dbSNP	6025
HapMap	6025
SNPedia	6025
ALFRED	SI001216K

Factor V Leiden is anautosomal dominantgenetic condition that exhibits incompletepenetrance,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 activated protein C. Thegenethat codes the protein is referred to asF5.Mutationof thisgene—asingle nucleotide polymorphism(SNP) is located inexon10.As amissense substitutionof amino acid R to amino acid Q, it changes theprotein'samino acidfromargininetoglutamine.Depending on the chosen start the position of the nucleotide variant is either at position 1691 or 1746.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 activated protein C, 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 theveins,where the clotting may cause adeep vein thrombosis(DVT). If the venous clots break off, these clots can travel through the right side of theheartto thelungwhere they block apulmonary blood vesseland cause apulmonary embolism.It is extremely rare for this disorder to cause the formation of clots in arteries that can lead tostrokeorheart attack,though a "mini-stroke", known as atransient ischemic attack,is more common. Given that this disease displaysincomplete dominance,those who arehomozygousfor the mutatedalleleare at a heightened risk for the events detailed above versus those who areheterozygousfor 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 anaPTTbased 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 and the other, in the absence. A ratio is determined based on the two tests and the results signify to the laboratory whether activated protein C 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 therestriction endonucleaseMnlI,soPCR,treatment withMnlI,and thenDNA electrophoresiswill 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.Anticoagulantsare not routinely recommended for people withheterozygousfactor V Leiden, unless there are additional risk factors present, but are given when such an event occurs.A single occurrence ofdeep vein thrombosisorpulmonary embolismin people with factor V Leiden warrants temporary anticoagulant treatment, but generally not lifelong treatment.In addition, temporary treatment with an anticoagulant such asheparinmay be required during periods of particularly high risk of thrombosis, such as major surgery.People withhomozygousfactor V Leiden or heterozygous factor V Leiden with additional thrombophilia however should be considered for lifelongoralanticoagulation.

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.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."Up to 30 percent of patients who present withdeep vein thrombosis(DVT) orpulmonary embolismhave 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.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 3 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 forrecurrentvenous thrombosis. While only 1 percent of people with factor V Leiden have two copies of the defective gene, thesehomozygousindividuals have a more severe clinical condition. The presence of acquired risk factors for venous thrombosis—includingsmoking,use of estrogen-containing (combined) forms ofhormonal contraception,and recentsurgery—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 inpregnancy(and onestrogen-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 ofpreeclampsia,may have a small increased risk of low birth weight babies, may have a small increased risk ofmiscarriageandstillbirthdue 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.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

• Prothrombin G20210A

Further reading

• Herskovits AZ, Lemire SJ, Longtine J, Dorfman DM (November 2008)."Comparison of Russell viper venom-based and activated partial thromboplastin time-based screening assays for resistance to activated protein C".American Journal of Clinical Pathology.130(5): 796–804.doi:10.1309/AJCP7YBJ6URTVCWP.PMID18854273.
• Press RD, Bauer KA, Kujovich JL, Heit JA (November 2002)."Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders".Archives of Pathology & Laboratory Medicine.126(11): 1304–18.doi:10.5858/2002-126-1304-CUOFVL.PMID12421138.
• Hooper WC, De Staercke C (2002)."The relationship between FV Leiden and pulmonary embolism".Respiratory Research.3(1): 8.doi:10.1186/rr180.PMC64819.PMID11806843.
• Nicolaes GA, Dahlbäck B (April 2002). "Factor V and thrombotic disease: description of a janus-faced protein".Arteriosclerosis, Thrombosis, and Vascular Biology.22(4): 530–8.doi:10.1161/01.ATV.0000012665.51263.B7.PMID11950687.S2CID13215200.
• Andreassi MG, Botto N, Maffei S (2006). "Factor V Leiden, prothrombin G20210A substitution and hormone therapy: indications for molecular screening".Clinical Chemistry and Laboratory Medicine.44(5): 514–21.doi:10.1515/CCLM.2006.103.PMID16681418.S2CID34399027.
• Segers K, Dahlbäck B, Nicolaes GA (September 2007)."Coagulation factor V and thrombophilia: background and mechanisms".Thrombosis and Haemostasis.98(3): 530–42.doi:10.1160/th07-02-0150.PMID17849041.S2CID29406966.Archived fromthe originalon 2013-02-11.
• Kujovich J; Pagon, RA; Bird, TC; Dolan, CR; Stephens, K (2010) [1999]."Factor V Leiden Thrombophilia".GeneReviews.PMID20301542.

• factor+V+Leidenat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
• Kujovich JL, Goodnight SH (2007-02-17)."Factor V Leiden Thrombophilia".GeneReviews.University of Washington, Seattle. Archived fromthe originalon 2008-06-02.Retrieved2008-06-20.
• Factor V Leiden Thrombophilia Explained - Genome.gov