Factor V Leiden
Factor V Leiden is the most common hereditary blood coagulation disorder in the United States. It is present in 5% of the Caucasian population and ~1% of the African-American population. The condition is caused by a mutation in the gene that codes for clotting Factor V. Normally, FV acts as an accelerator of the clotting process. After coagulation is underway, FV activity is reduced by Activated Protein C, which cleaves FV at three distinct sites on its polypeptide chain. The most important of these cleavage sites resides at position 506. In Factor V Leiden, the Arginine residue normally at this position is replaced by Glutamic Acid. Thus, inactivation of FV is impaired and the failure to substantially reduce thrombin generation results in a hypercoagulable state.
Factor V Leiden increases the risk of venous thrombosis 3-8 fold for heterozygous and 30-100 fold for homozygous individuals. Importantly, this common defect may substantially increase the thrombotic risk when present with other congenital and acquired risk factors (e.g. the Prothrombin 20210 mutation, Protein S and C deficiency, hyperhomocystenemia, oral contraceptives, surgery, obesity, metabolic disorders).
Factor V Leiden is associated with venous thrombosis, including pulmonary embolism, and may be a factor in recurrent abortion and some arterial thrombotic events, including stroke and myocardial infarction.
Treatment of a patient with Factor V Leiden depends upon the individual patient's risk of recurrent thromboembolic disease. Typically, this will include the use of heparin, followed by oral anticoagulant for 3 - 6 months. The duration of therapy will depend on the clinical picture of thrombosis and is not usually influenced by heterozygous FV Leiden per se. Long term continuation of oral anticoagulants is generally not indicated in Factor V Leiden heterozygotes after a single thromboembolic episode given the risk of bleeding associated with anticoagulation. In contrast, patients that have had multiple thromboembolic episodes or are at high risk of further episodes (for example, multiple thrombotic risk factors or Factor V Leiden homozygotes) would be candidates for long-term anticoagulation.
The presence of FV Leiden is suggested by the finding of Resistance to Activated Protein C in a clotting-based screening assay. More than 95% of such cases are due to FV Leiden. However, the Hemostasis and Thrombosis Laboratory recommends that the diagnosis be confirmed by a specific genetic test, which can also indicate whether the affected individual is heterozygous or homozygous for the defect. The Hemostasis and Thrombosis laboratory uses Nanosphere’s Verigene F5 Nucleic acid test to detect and genotype a single point mutation (G to A at position 1691) of the human factor V gene. This assay is a DNA microarray signal amplification assay using Nanosphere’s gold nanoparticle technology.
It should be noted that the functional assay of FV clotting activity is not helpful in the exclusion of FV Leiden. Rarely, however, a condition known as pseudohomozygous FV Leiden may be present. This is caused by the co-inheritance of FV Leiden and FV deficiency - in effect a double heterozygote. These patients have 50% normal FV levels and because their only normal FV allele carries the FV Leiden mutation, they are phenotypically homozygotes for this condition.
