Factor V Leiden

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Factor V Leiden thrombophilia
Specialty Hematology

Factor V Leiden (rs6025 or F5p.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 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. [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 of Leiden, where it was first identified in 1994 by Rogier Maria Bertina under the direction of (and in the laboratory of) Pieter Hendrick Reitsma. [6] Despite the increased risk of venous thromboembolisms, people with one copy of this gene have not been found to have shorter lives than the general population. [7] It is an autosomal dominant genetic disorder with incomplete penetrance.

Contents

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.[ citation needed ]

Symptoms of factor V Leiden include:[ citation needed ]

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.[ citation needed ]

Pathophysiology

In the normal pathway, 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 is a natural anticoagulant that acts to limit the extent of clotting by cleaving and degrading factor V.[ citation needed ]

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 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 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. [10]

The excessive clotting that occurs in this disorder is almost always restricted to the veins, [11] 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. [12]

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 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 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

As there is no cure yet, treatment is focused on prevention of thrombotic complications. Anticoagulants are not routinely recommended for people with heterozygous factor V Leiden, unless there are additional risk factors present, but are given when such an event occurs. [13] [14] [15] 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. [13] 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. [13] [15] People with homozygous factor V Leiden or heterozygous factor V Leiden with additional thrombophilia however should be considered for lifelong oral anticoagulation. [15]

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. [16] [17] 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." [18] 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. [19] 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. [20] 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.[ citation needed ]

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. [21] 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.[ citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">Thrombosis</span> Medical condition caused by blood clots

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Thrombus</span> Blood clot

A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through healthy blood vessels in the circulatory system.

<span class="mw-page-title-main">Pulmonary embolism</span> Blockage of an artery in the lungs

Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathing in, and coughing up blood. Symptoms of a blood clot in the leg may also be present, such as a red, warm, swollen, and painful leg. Signs of a PE include low blood oxygen levels, rapid breathing, rapid heart rate, and sometimes a mild fever. Severe cases can lead to passing out, abnormally low blood pressure, obstructive shock, and sudden death.

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

<span class="mw-page-title-main">Deep vein thrombosis</span> Formation of a blood clot (thrombus) in a deep vein

Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms. The most common life-threatening concern with DVT is the potential for a clot to embolize, travel as an embolus through the right side of the heart, and become lodged in a pulmonary artery that supplies blood to the lungs. This is called a pulmonary embolism (PE). DVT and PE comprise the cardiovascular disease of venous thromboembolism (VTE). About two-thirds of VTE manifests as DVT only, with one-third manifesting as PE with or without DVT. The most frequent long-term DVT complication is post-thrombotic syndrome, which can cause pain, swelling, a sensation of heaviness, itching, and in severe cases, ulcers. Recurrent VTE occurs in about 30% of those in the ten years following an initial VTE.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism and in the treatment of myocardial infarction.

D-dimer is a dimer that is a fibrin degradation product, a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein joined by a cross-link, hence forming a protein dimer.

<span class="mw-page-title-main">Protein S deficiency</span> Medical condition

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the degradation of factor Va and factor VIIIa.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

<span class="mw-page-title-main">Factor V</span> Mammalian protein found in humans

Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations predispose for thrombosis.

The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (factor II), an inactive zymogen, to thrombin (factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

An embolus, is described as a free-floating mass, located inside blood vessels that can travel from one site in the blood stream to another. An embolus can be made up of solid, liquid, or gas. Once these masses get "stuck" in a different blood vessel, it is then known as an "embolism." An embolism can cause ischemia—damage to an organ from lack of oxygen. A paradoxical embolism is a specific type of embolism in which the embolus travels from the right side of the heart to the left side of the heart and lodges itself in a blood vessel known as an artery. Thus, it is termed "paradoxical" because the embolus lands in an artery, rather than a vein.

<span class="mw-page-title-main">Activated protein C resistance</span> Medical condition

Activated protein C resistance (APCR) is a hypercoagulability characterized by a lack of a response to activated protein C (APC), which normally helps prevent blood from clotting excessively. This results in an increased risk of venous thrombosis, which resulting in medical conditions such as deep vein thrombosis and pulmonary embolism. The most common cause of hereditary APC resistance is factor V Leiden mutation.

<span class="mw-page-title-main">Protein C deficiency</span> Medical condition

Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981. The disease belongs to a group of genetic disorders known as thrombophilias. Protein C deficiency is associated with an increased incidence of venous thromboembolism, whereas no association with arterial thrombotic disease has been found.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

<span class="mw-page-title-main">Apixaban</span> Anticoagulant medication

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. Specifically, it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests or dietary restrictions. It is taken by mouth.

Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism. One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000. Two copies increases the risk to up to 20 in 1,000 per year. Most people never develop a blood clot in their lifetimes.

<span class="mw-page-title-main">Superficial vein thrombosis</span> Medical condition

Superficial vein thrombosis (SVT) is a blood clot formed in a superficial vein, a vein near the surface of the body. Usually there is thrombophlebitis, which is an inflammatory reaction around a thrombosed vein, presenting as a painful induration with redness. SVT itself has limited significance when compared to a deep vein thrombosis (DVT), which occurs deeper in the body at the deep venous system level. However, SVT can lead to serious complications, and is therefore no longer regarded as a benign condition. If the blood clot is too near the saphenofemoral junction there is a higher risk of pulmonary embolism, a potentially life-threatening complication.

<span class="mw-page-title-main">Thrombosis prevention</span> Medical treatment

Thrombosis prevention or thromboprophylaxis is medical treatment to prevent the development of thrombosis in those considered at risk for developing thrombosis. Some people are at a higher risk for the formation of blood clots than others, such as those with cancer undergoing a surgical procedure. Prevention measures or interventions are usually begun after surgery as the associated immobility will increase a person's risk.

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. Archived from the original (PDF) on 2020-01-28. Retrieved 2020-01-28.
  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. S2CID   45534038.
  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. ↑ Juul, Klaus; Tybjærg-Hansen, Anne; Steffensen, Rolf; Kofoed, Steen; Jensen, Gorm; Nordestgaard, Børge Grønne (2002-07-01). "Factor V Leiden: The Copenhagen City Heart Study and 2 meta-analyses". Blood. 100 (1): 3–10. doi: 10.1182/blood-2002-01-0111 . ISSN   1528-0020. PMID   12070000. S2CID   9556602.
  11. ↑ Ng, N; Brown, JRI; Edmondson, RA; Tillyer, Ml (May 2000). "LESSON OF THE MONTH – Catastrophic Arterial Thromboembolism Associated with Factor V Leiden". European Journal of Vascular and Endovascular Surgery. 19 (5): 551–553. doi: 10.1053/ejvs.1999.0971 . PMID   10828239.
  12. ↑ "Factor V Leiden Mutation – Homozygous" (PDF).
  13. 1 2 3 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.
  14. ↑ 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.
  15. 1 2 3 Nichols WL, Heit JA (September 1996). "Activated protein C resistance and thrombosis". Mayo Clin Proc. 71 (9): 897–8. doi:10.4065/71.9.897. PMID   8790269.
  16. ↑ Ridker, et al. "Ethnic distribution of factor V Leiden in 4047 men and women". Supra.
  17. ↑ Gregg, et al. "Prevalence of the factor V-Leiden mutation in four distinct American ethnic populations". Supra.
  18. ↑ Id.
  19. ↑ What do we know about heredity and factor V Leiden thrombophilia? http://www.genome.gov/15015167#Q5
  20. ↑ "Factor V Leiden thrombophilia: MedlinePlus Genetics".
  21. ↑ 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.

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