Factor V Leiden mutation

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 (The Netherlands), where it was first identified in 1994 by Prof R. Bertina et al.


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 in which the coagulation factor cannot be destroyed by aPC. The gene that codes the protein is referred to a 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 affect 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 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 rare a "mini-stroke" known as a transient ischemic attack is more common .


Studies have found that about 5% 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% of patients who present with deep vein thrombosis (DVT) or pulmonary embolism have this condition. Factor V Leiden doubles the risk that a person will have a DVT during their life, but it is unclear whether these individuals are at increased risk for recurrent venous thrombosis. While only 1% 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 have an increased risk of preeclampsia, as well as miscarriage and stillbirth due to clotting in the placenta, umbilical cord, or the fetus (fetal clotting may depend on whether the baby has inherited the gene). Note that many of these women go through one or more pregnancies with no difficulties, while others may miscarry over and over again, and still others may develop clots within weeks of becoming pregnant.


Suspicion of factor V Leiden being the cause for any thrombotic event should be considered in any white patient below the age of 45, or in any person with a family history of venous thrombosis.

This disease can be diagnosed by watching the aPTT (the time it takes for blood to clot) as activated protein C is added. With a normal patient, adding aPC increases the aPTT. In patients with factor V Leiden, adding aPC will barely affect the time it takes for blood to clot.

There is also a simple 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 simple PCR, treatment with MnlI, and then DNA electrophoresis will give a quick diagnosis.


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