Factor V Leiden - Pathophysiology

Pathophysiology

In the normal person, factor V functions as a cofactor to allow factor Xa to activate an enzyme called 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.

Factor V Leiden is an autosomal dominant condition that exhibits incomplete dominance and 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. 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.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.