Factor V Leiden
Encyclopedia
Factor V Leiden is the name given to a variant of human factor V
that causes a hypercoagulability
disorder. In this disorder the Leiden variant of factor V
cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder
amongst Eurasia
ns. It is named after the city Leiden (Netherlands
), where it was first identified in 1994 by Prof R. Bertina et al.
to allow factor X
to activate an enzyme
called thrombin
. Thrombin in turn cleaves fibrinogen
to 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.
Factor V Leiden is an autosomal dominant condition which exhibits incomplete dominance and results in a factor V variant which 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.
As a missense substitution it changes a 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.
It also affects the amino acid position for the variant which is either 506 or 534.
Together with the general lack of nomenclature standard it means that the SNP can be referred to in several ways such as
G1691A, c.1601G>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 excess fibrin generation 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
. Women with the disorder have an increased risk of miscarriage and stillbirth. 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.
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. 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 1 in 250 to 1 in 125. Having two copies of the mutation may raise the risk as high as 1 in 12.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
use, 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. 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.
There are a few different methods by which this disease 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 shortened 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.
Factor V
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...
that causes a hypercoagulability
Thrombophilia
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...
disorder. In this disorder the Leiden variant of factor V
Factor V
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...
cannot be inactivated by activated protein C. Factor V Leiden is the most common hereditary hypercoagulability disorder
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
amongst Eurasia
Eurasia
Eurasia is a continent or supercontinent comprising the traditional continents of Europe and Asia ; covering about 52,990,000 km2 or about 10.6% of the Earth's surface located primarily in the eastern and northern hemispheres...
ns. It is named after the city Leiden (Netherlands
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...
), where it was first identified in 1994 by Prof R. Bertina et al.
Pathophysiology
In the normal person, factor V functions as a cofactorCofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
to allow factor X
Factor X
Factor X, also known by the eponym Stuart-Prower factor or as prothrombinase, is an enzyme of the coagulation cascade. It is a serine endopeptidase .-Physiology:...
to activate an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
called thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
. Thrombin in turn cleaves fibrinogen
Fibrinogen
Fibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
to fibrin
Fibrin
Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....
, which polymerizes to form the dense meshwork that makes up the majority of a clot. Activated protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
(aPC) is a natural anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
that acts to limit the extent of clotting by cleaving and degrading factor V.
Factor V Leiden is an autosomal dominant condition which exhibits incomplete dominance and results in a factor V variant which cannot be as easily degraded by aPC (activated Protein C
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
).
The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that codes the protein is referred to as F5.
Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of this gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
—a single nucleotide polymorphism
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
(SNP) is located in exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
10.
As a missense substitution it changes a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
's amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
from arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
to glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
.
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 it means that the SNP can be referred to in several ways such as
G1691A, c.1601G>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 excess fibrin generation 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
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
(DVT). If the venous clots break off, these clots can travel through the right side of the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
to the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
, where they block a pulmonary blood vessel
Pulmonary blood vessel
The pulmonary blood vessels are those blood vessels which carry blood to and from the lungs.The pulmonary arteries, which carry blood from the heart to the lungs, are the only arteries which carry deoxygenated blood. Conversely, the pulmonary veins, carrying blood from the lungs to the left atrium...
and cause a pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
. Women with the disorder have an increased risk of miscarriage and stillbirth. It is extremely rare for this disorder to cause the formation of clots in arteries that can lead to stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, though a "mini-stroke", known as a transient ischemic attack
Transient ischemic attack
A transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...
, is more common . Given that this disease displays incomplete dominance, those who are homozygous for the mutated allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
are at a heightened risk for the events detailed above versus those that are heterozygous for the mutation.
Epidemiology
Studies have found that about 5 percent of Caucasians in North America have factor V Leiden. The disease is less common in Hispanics and African-Americans and is extremely rare in people of Asian descent.Up to 30 percent of patients who present with deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
(DVT) or pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
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. 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 1 in 250 to 1 in 125. Having two copies of the mutation may raise the risk as high as 1 in 12.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
Tobacco smoking
Tobacco smoking is the practice where tobacco is burned and the resulting smoke is inhaled. The practice may have begun as early as 5000–3000 BCE. Tobacco was introduced to Eurasia in the late 16th century where it followed common trade routes...
, use of estrogen-containing (combined) forms of hormonal contraception
Hormonal contraception
Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The original hormonal method—the combined oral contraceptive...
use, and recent surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
—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
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
(and on estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
-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
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
and stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
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. 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.
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 disease can be diagnosed. Most laboratories screen 'at risk' patients with either a snake venom (e.g. dilute Russell's viper venom time
Dilute Russell's viper venom time
Dilute Russell's viper venom time is a laboratory test often used for detection of lupus anticoagulant .Variations in the test can affect the results.-Mechanism:...
) based test or an aPTT based test. In both methods, the time it takes for blood to clot is shortened 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
Protein C
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogenic protein, the activated form of which plays an important role in regulating blood clotting, inflammation, cell death and maintaining the permeability of blood vessel walls in humans and other animals...
(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
DNA electrophoresis
Nucleic acid electrophoresis is an analytical technique used to separate DNA or RNA fragments by size and reactivity. Nucleic acid molecules which are to be analyzed are set upon a viscous medium, the gel, where an electric field induces the nucleic acids to migrate toward the anode, due to the net...
will give a diagnosis.