LabMed

Factor V Leiden Mutation

At a Glance

Factor V Leiden is an inherited venous thrombotic disorder. A history of unexplained venous thrombosis in a patient less than 50 years of age with a family history of venous thrombosis should prompt consideration for factor V Leiden. First, venous thrombosis with heterozygous factor V Leiden typically occurs in otherwise healthy individuals at approximately 40 years of age. Thrombosis may be triggered by surgery, trauma, pregnancy or prolonged immobilization, such as car or plane rides longer than 8 hours. Venous thrombosis associated with factor V Leiden may occur in unusual locations, such as the portal vein, mesenteric vein, superior sagittal sinus or arm veins, and in multiple veins simultaneously. Any of these indicators of unusual venous thrombosis should prompt consideration of factor V Leiden.

Factor V Leiden occurs in about 5% of Caucasians but is rare in individuals of African, Hispanic, or Asian descent. Patients with factor V Leiden are typically heterozygotes with 1 normal factor V gene and 1 abnormal factor V Leiden gene, resulting in an autosomal dominant heredity pattern (male and female, each generation showing disorder). Approximately 1 in 400 Caucasians are homozygous for factor V Leiden, which has a much stronger association with venous thrombotic risk.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Two tests can be used to detect factor V Leiden: DNA testing for the factor V Leiden mutation and clot-based activated protein C resistance assays. Factor V Leiden DNA assays can determine whether the patient has two normal factor V genes and whether the patient is heterozygous for the factor V Leiden mutation or homozygous for the mutation.

In normal individuals, the activated form of protein C destroys the activated form of factor V to prevent excessive clot formation away from the site of a wound. The factor V Leiden mutation prevents activated protein C from destroying activated factor V. Activated protein C resistance assays measure the ability of activated protein C to destroy factor V in the patient’s plasma. Current generation activated protein C resistance assays give similar results to factor V Leiden assays in most patients and can determine whether the patient is likely heterozygous or homozygous for factor V mutations.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Rare individuals have mutations of their factor V gene that alter cleavage of factor V by activated protein C but are different than the factor V Leiden mutation (e.g. factor V Hong Kong and factor V Cambridge). Most factor V Leiden genetic assays will not detect these mutations, but they are rare and their association with thrombotic risk is less well established than factor V Leiden.

The majority of plasma factor V is made in the liver. Most genetic tests for factor V Leiden evaluate DNA purified from white blood cells. Patients with bone marrow or liver transplants may show discrepancies between the factor V gene evaluated in white cell DNA and the factor V in plasma being produced by the liver. In bone marrow or liver transplant patients, the activated protein C resistance assay can be used to assess the factor V produced by the liver.

Some activated protein C resistance assays may suffer interference from lupus inhibitors, factor V deficiency, heparin or low molecular weight heparin, and direct thrombin inhibitors. Patients should be off anticoagulant medications for at least 10 days prior to measuring activated protein C resistance. The factor V Leiden DNA test is preferable for patients with strong lupus inhibitors, low factor V levels or other conditions that may interfere with the activated protein C resistance assay.

What Lab Results Are Absolutely Confirmatory?

If positive, genetic testing for the factor V Leiden mutation is definitive if the patient has not had a liver or bone marrow transplant. Negative results on genetic testing for factor V Leiden is usually definitive in Caucasians, with the exception of transplant patients and other rare factor V mutations.

Does factor V Leiden predict initial or recurrent venous thrombosis or change recommendations for antithrombotic therapy?

Patients heterozygous for factor V Leiden have approximately a 2- to 5-fold increased risk of developing venous thrombosis compared to individuals without inherited thrombophilia and tend to develop venous thrombosis at a younger age, but most individuals with factor V Leiden never develop venous thrombosis. Patients homozygous for factor V Leiden have a 10- to 50-fold increased risk of venous thrombosis. Factor V Leiden is associated with an increased risk of fetal loss and venous thrombosis during pregnancy. Testing for factor V Leiden does not, in practice, identify individuals who will definitely develop recurrent venous thrombosis, reduce the incidence of recurrent venous thrombosis, or alter antithrombotic therapy in most cases.

Because the prevalence of factor V Leiden is so high in Caucasians, coinheritance with other inherited and acquired thrombotic risk factors must be considered when evaluating patients with a strong family history of venous thrombosis. Multiple risk factors tend to increase the overall risk of venous thrombosis. For example factor V Leiden and oral contraceptive use together have a higher risk of venous thrombosis than either alone.

Additional issues of Clinical Importance

Factor V Leiden is, generally, not associated with an increased risk of thrombosis in children prior to puberty unless they also have other risk factors for venous thrombosis, such as cancer, infection or intravascular catheters.

The association between factor V Leiden and arterial thrombosis is weak, controversial, and has no therapeutic implications at present.

Errors in test selection and interpretation

Common errors include ordering a “factor V activity” rather than a factor V Leiden DNA or ordering “protein C activity” instead of an activated protein C resistance assay.

Patients with bone marrow or liver transplants may show discrepancies between the factor V gene evaluated in white cell DNA and the factor V in plasma produced by the liver. In bone marrow or liver transplant patients, the activated protein C resistance assay can be used to assess the factor V produced by the liver.

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