Factor V Leiden

Factor V Leiden (sometimes factor VLeiden) 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 Eurasians. It is named after the city Leiden (Netherlands), where it was first identified in 1994 by Prof R. Bertina et al.

Pathophysiology
In the normal person, factor V functions as a cofactor 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.

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 (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.

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) 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.