Factor V Leiden thrombophilia

Factor V Leiden thrombophilia

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Factor V Leiden thrombophilia

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Description

Factor V Leiden thrombophilia is an inherited disorder of blood clotting . Factor V Leiden is the name of a specific gene mutation that results in thrombophilia, which is an increased tendency to form abnormal blood clots that can block blood vessels.

People with factor V Leiden thrombophilia have a higher than average risk of developing a type of blood clot called a deep venous thrombosis (DVT). DVTs occur most often in the legs, although they can also occur in other parts of the body, including the brain, eyes, liver, and kidneys. Factor V Leiden thrombophilia also increases the risk that clots will break away from their original site and travel through the bloodstream. These clots can lodge in the lungs, where they are known as pulmonary emboli . Although factor V Leiden thrombophilia increases the risk of blood clots, only about 10 percent of individuals with the factor V Leiden mutation ever develop abnormal clots.

The factor V Leiden mutation is associated with a slightly increased risk of pregnancy loss (miscarriage). Women with this mutation are two to three times more likely to have multiple (recurrent) miscarriages or a pregnancy loss during the second or third trimester. Some research suggests that the factor V Leiden mutation may also increase the risk of other complications during pregnancy, including pregnancy-induced high blood pressure ( preeclampsia ), slow fetal growth, and early separation of the placenta from the uterine wall (placental abruption). However, the association between the factor V Leiden mutation and these complications has not been confirmed. Most women with factor V Leiden thrombophilia have normal pregnancies.

Related Information

  • What does it mean if a disorder seems to run in my family?
  • What is the prognosis of a genetic condition?
  • Genetic and Rare Diseases Information Center

Frequency

Factor V Leiden is the most common inherited form of thrombophilia. Between 3 and 8 percent of people with European ancestry carry one copy of the factor V Leiden mutation in each cell, and about 1 in 5,000 people have two copies of the mutation. The mutation is less common in other populations.

Related Information

  • What information about a genetic condition can statistics provide?
  • Why are some genetic conditions more common in particular ethnic groups?

Causes

A particular mutation in the F5 gene causes factor V Leiden thrombophilia. The F5 gene provides instructions for making a protein called coagulation factor V. This protein plays a critical role in the coagulation system, which is a series of chemical reactions that forms blood clots in response to injury.

The coagulation system is controlled by several proteins, including a protein called activated protein C (APC). APC normally inactivates coagulation factor V, which slows down the clotting process and prevents clots from growing too large. However, in people with factor V Leiden thrombophilia, coagulation factor V cannot be inactivated normally by APC. As a result, the clotting process remains active longer than usual, increasing the chance of developing abnormal blood clots.

Other factors also increase the risk of developing blood clots in people with factor V Leiden thrombophilia. These factors include increasing age, obesity, injury, surgery, smoking, pregnancy, and the use of oral contraceptives (birth control pills) or hormone replacement therapy. The risk of abnormal clots is also much higher in people who have a combination of the factor V Leiden mutation and another mutation in the F5 gene. Additionally, the risk is increased in people who have the factor V Leiden mutation together with a mutation in another gene involved in the coagulation system.

Learn more about the gene associated with factor V Leiden thrombophilia

  • F5

Related Information

  • What is a gene?
  • What is a gene mutation and how do mutations occur?
  • How can gene mutations affect health and development?
  • More about Mutations and Health

Inheritance Pattern

The chance of developing an abnormal blood clot depends on whether a person has one or two copies of the factor V Leiden mutation in each cell. People who inherit two copies of the mutation, one from each parent, have a higher risk of developing a clot than people who inherit one copy of the mutation. Considering that about 1 in 1,000 people per year in the general population will develop an abnormal blood clot, the presence of one copy of the factor V Leiden mutation increases that risk to 3 to 8 in 1,000, and having two copies of the mutation may raise the risk to as high as 80 in 1,000.

Related Information

  • What does it mean if a disorder seems to run in my family?
  • What are the different ways in which a genetic condition can be inherited?
  • More about Inheriting Genetic Conditions

Diagnosis & Management Links

Genetic Testing Information (4 links)

  • What is genetic testing?
  • American College of Medical Genetics and Genomics Consensus Statement on Factor V Leiden Mutation Testing (PDF)
  • Genetic Testing Registry: Thrombophilia due to activated protein C resistance
  • Genetic Testing Registry: Thrombophilia due to factor V Leiden

Research Studies from ClinicalTrials.gov (1 link)

  • ClinicalTrials.gov

Other Diagnosis and Management Resources (3 links)

  • GeneReview: Factor V Leiden Thrombophilia
  • MedlinePlus Encyclopedia: Deep Venous Thrombosis
  • MedlinePlus Encyclopedia: Pulmonary Embolus

Related Information

  • How we cover diagnosis and management of health conditions
  • How are genetic conditions diagnosed?
  • How are genetic conditions treated or managed?
  • How can I find a genetics professional in my area?

Other Names for This Condition

  • APC resistance, Leiden type
  • Hereditary resistance to activated protein C

Related Information

  • How are genetic conditions and genes named?

Additional Information & Resources

Health Information from MedlinePlus (3 links)

  • Encyclopedia: Deep Venous Thrombosis
  • Encyclopedia: Pulmonary Embolus
  • Health Topic: Blood Clots

Genetic and Rare Diseases Information Center (1 link)

  • Factor V Leiden thrombophilia

Additional NIH Resources (3 links)

  • National Center for Biotechnology Information: Mutations and Blood Clots
  • National Heart, Lung, and Blood Institute: Deep Vein Thrombosis
  • National Human Genome Research Institute

Educational Resources (3 links)

  • Factor V Leiden Cardiology Patient Page
  • MalaCards: factor v leiden thrombophilia
  • The Merck Manual Home Edition for Patients and Caregivers

Patient Support and Advocacy Resources (2 links)

  • National Blood Clot Alliance
  • Resource list from the University of Kansas Medical Center

Clinical Information from GeneReviews (1 link)

  • Factor V Leiden Thrombophilia

Scientific Articles on PubMed (1 link)

  • PubMed

Catalog of Genes and Diseases from OMIM (1 link)

  • THROMBOPHILIA DUE TO ACTIVATED PROTEIN C RESISTANCE

Sources for This Page

  • Calderwood CJ, Greer IA. The role of factor V Leiden in maternal health and the outcome of pregnancy. Curr Drug Targets. 2005 Aug;6(5):567-76. Review.
    Citation on PubMed
  • Horne MK 3rd, McCloskey DJ. Factor V Leiden as a common genetic risk factor for venous thromboembolism. J Nurs Scholarsh. 2006;38(1):19-25. Review.
    Citation on PubMed
  • Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004 Mar 2;140(5):330-7.
    Citation on PubMed
  • Kujovich JL. Factor V Leiden Thrombophilia. 1999 May 14 [updated 2010 Mar 9]. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from http://www.ncbi.nlm.nih.gov/books/NBK1368/
    Citation on PubMed
  • Major DA, Sane DC, Herrington DM. Cardiovascular implications of the factor V Leiden mutation. Am Heart J. 2000 Aug;140(2):189-95. Review.
    Citation on PubMed
  • Mann KG, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde. Blood. 2003 Jan 1;101(1):20-30. Epub 2002 Aug 8. Review.
    Citation on PubMed
  • Ornstein DL, Cushman M. Cardiology patient page. Factor V Leiden. Circulation. 2003 Apr 22;107(15):e94-7.
    Citation on PubMed
  • Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost. 2009 Jul;7 Suppl 1:301-4. doi: 10.1111/j.1538-7836.2009.03394.x. Review.
    Citation on PubMed
  • Rosendorff A, Dorfman DM. Activated protein C resistance and factor V Leiden: a review. Arch Pathol Lab Med. 2007 Jun;131(6):866-71. Review.
    Citation on PubMed
  • 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 Jun 17;301(23):2472-85. doi: 10.1001/jama.2009.853. Review.
    Citation on PubMed

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Reviewed : August 2010

Published : November 27, 2018

The resources on this site should not be used as a substitute for professional medical care or advice. Users with questions about a personal health condition should consult with a qualified healthcare professional .

Factor V Leiden

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Factor V Leiden thrombophilia
Specialty Hematology

Factor V Leiden (rs6025) 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 ). With 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. [1] Factor V Leiden is the most common hereditary hypercoagulability (prone to clotting) disorder amongst ethnic Europeans. [2] [3] [4] 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. [5]

Contents

  • 1 Signs and symptoms
  • 2 Pathophysiology
  • 3 Diagnosis
  • 4 Management
  • 5 Epidemiology
  • 6 See also
  • 7 References
  • 8 Further reading
  • 9 Further reading
  • 10 External links

Signs and symptoms[ edit ]

Abnormal, recurrent venous thromboses.

Pathophysiology[ edit ]

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
Gene Factor V
Chromosome 1
External databases
Ensembl Human SNPView
dbSNP 6025
HapMap 6025
SNPedia 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. [6] 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. [7] 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[ edit ]

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.[ citation needed ]

Management[ edit ]

As there is no cure, treatment is focused on prevention of thrombotic complications by counseling. Standard treatment includes lifelong treatment with an anticoagulant such as warfarin and constant evaluation (blood testing) of the effectiveness of that anticoagulant. 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. [8]

Epidemiology[ edit ]

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. [9] [10] 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.” [11]

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. [12] 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. [13] 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[ edit ]

  • Prothrombin G20210A

References[ edit ]

  1. ^ 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 .

  2. ^ 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 .
  3. ^ 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 .
  4. ^ 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 .
  5. ^ 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 .
  6. ^ “SNP linked to Gene F5” . NCBI.
  7. ^ Jennifer Bushwitz; Michael A. Pacanowski & Julie A. Johnson (2006-10-11). “Important Variant Information for F5” . PharmGKB .
  8. ^ Factor V Leiden. Circulation. http://circ.ahajournals.org/content/107/15/e94
  9. ^ Ridker, et al. “Ethnic distribution of factor V Leiden in 4047 men and women”. Supra.
  10. ^ Gregg, et al. “Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations”. Supra.
  11. ^ Id.
  12. ^ What do we know about heredity and factor V Leiden thrombophilia? http://www.genome.gov/15015167#Q5
  13. ^ 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[ edit ]

  • 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 . PMID   18854273 .
  • 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 : 10.1043/0003-9985(2002)126<1304:CUOFVL>2.0.CO;2 . PMID   12421138 .
  • Hooper WC, De Staercke C (2002). “The relationship between FV Leiden and pulmonary embolism” . Respiratory Research. 3 (1): 8. doi : 10.1186/rr180 . PMC   64819 . PMID   11806843 .
  • 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 . PMID   11950687 .
  • 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 . PMID   16681418 .
  • 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 . PMID   17849041 .
  • Kujovich J; Pagon, RA; Bird, TC; Dolan, CR; Stephens, K (2010) [1999]. “Factor V Leiden Thrombophilia” . GeneReviews. PMID   20301542 .

Further reading[ edit ]

  • factor+V+Leiden at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Kujovich JL, Goodnight SH (2007-02-17). “Factor V Leiden Thrombophilia” . GeneReviews. University of Washington, Seattle. Archived from the original on 2008-06-02. Retrieved 2008-06-20.

External links[ edit ]

Classification
D
  • ICD – 10 : D68.51
  • ICD – 9-CM : 289.81
  • OMIM : 188055
  • DiseasesDB : 154

  • v
  • t
  • e
Diseases of clotting ( D50–69,74 , 280–287 )
Coagulation /
coagulopathy
Hyper-
coagulability
  • primary: Antithrombin III deficiency
  • Protein C deficiency / Activated protein C resistance / Protein S deficiency / Factor V Leiden
  • Prothrombin G20210A
  • Sticky platelet syndrome
  • acquired: Thrombocytosis
    • essential
  • DIC
    • Purpura fulminans
  • autoimmune
    • Antiphospholipid
Hypo-
coagulability
Thrombocytopenia
  • Thrombocytopenic purpura : ITP
    • Evans syndrome
  • TM
    • TTP
    • Upshaw Schulman syndrome
  • Heparin-induced thrombocytopenia
  • May–Hegglin anomaly
Platelet function
  • adhesion
    • Bernard–Soulier syndrome
  • aggregation
    • Glanzmann’s thrombasthenia
  • platelet storage pool deficiency
    • Hermansky–Pudlak syndrome
    • Gray platelet syndrome
Clotting factor
  • Hemophilia
    • A/VIII
    • B/IX
    • C/XI
  • von Willebrand disease
  • Hypoprothrombinemia/II
  • Factor VII deficiency
  • Factor X deficiency
  • Factor XII deficiency
  • Factor XIII deficiency
  • Dysfibrinogenemia
  • Congenital afibrinogenemia

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