Factor V Leiden thrombophilia

Definition

Factor V Leiden thrombophilia is a common genetic disorder that leads to a predisposition or increased chance to develop blood clots in the veins (venous thrombosis).

Description

Factor V Leiden thrombophilia is a disorder caused by an inherited change or mutation in the genetic instructions for making a substance called factor V. The factor V change leads to an increased chance to develop blood clots in blood vessels.

Blood clots form in two steps. In the first step, the body produces platelets that are "sticky" and can form initial plugs or clots when needed. However, the first platelets only form the first temporary plugs. To form a more lasting plug or clot the platelets release chemicals to attract more platelets and other substances called clotting factors (or clotting proteins). In the second step, the platelets come together with the clotting proteins and form fibers. The fibers weave together and make the clot stronger and longer lasting.

Individuals affected by factor V Leiden thrombophilia have a genetic mutation that makes a longer lasting, "stickier" form of the clotting factor or protein called factor V. This different form of factor V is called factor V Leiden. The factor V Leiden clotting protein lasts longer in the blood because a chemical produced by the body called Activated Protein C (or APC), which is supposed to help "break-down" the factor V clotting protein, cannot break down the factor V Leiden clotting protein as easily and quickly as it breaks down normal factor V. The factor V Leiden clotting protein breaks down ten times slower than an average clotting factor V and accordingly stays in the blood longer.

Since there is longer lasting, extra sticky Factor V Leiden in the blood, individuals affected by factor V Leiden thrombophilia have an increased chance to have free-floating blood clots (thrombosis) that can get stuck in the veins and other blood vessels. An alternative name used to describe this condition is Hereditary Resistance to Activated Protein C.

Genetic profile

Factor V Leiden thrombophilia occurs when a specific gene on the long arm of chromosome one is changed or mutated. This gene is called F5. Every person has approximately 30,000-35,000 genes that tell our bodies how to form and function. Each gene is present in pairs, since one is inherited from the mother, and one is inherited from the father. Depending on the inheritance of the changed or mutated F5 gene, factor V Leiden thrombophilia runs in families in a more severe and less severe form.

The less severe form of factor V Leiden thrombophilia is called "heterozygous" and occurs when an individual inherits only one copy of the altered or mutated gene that causes factor V Leiden. The more severe form of factor V is called "homozygous" and is caused by the inheritance of two non-working or mutated copies of the gene that causes factor V Leiden thrombophilia.

Heterozygous factor V Leiden is inherited in an autosomal dominant pattern. In an autosomal dominant condition, only one changed or mutated copy of the gene for a particular condition is necessary for a person to experience symptoms of the condition. If a parent has an autosomal dominant condition, there is a 50% chance for each child to have the same or similar condition. In heterozygous factor V Leiden thrombophilia, the chance of being affected by venous blood clots is four to eight times greater than the general population.

Homozygous factor V Leiden thrombophilia is inherited in an autosomal recessive pattern. An autosomal recessive condition is caused by the inheritance of two changed or mutated copies of a gene. Individuals who are affected by heterozygous factor V Leiden thrombophilia have only one copy of the altered gene. However, when two people with heterozygous factor V Leiden thrombophilia have children together, there is a 25% chance, with each pregnancy, for the child to inherit two copies, one from each parent. That child then has two altered copies of the gene and therefore, has homozygous factor V Leiden thrombophilia. When an individual inherits two non-working copies of the gene that lead to homozygous factor V Leiden thrombophilia, there is an up to 80 times increased risk to be affected by blood clots stuck in the veins (venous thrombosis). Additionally, most individuals affected by homozygous factor V Leiden thrombophilia develop blood clots at a younger age than individuals affected by heterozygous factor V Leiden thrombophilia.

Demographics

Factor V Leiden thrombophilia is the most common inherited form of increased blood clotting in the general population. Factor V Leiden thrombophilia is more common in the Caucasian population. In the general U.S. and European population, heterozygous factor V Leiden thrombophilia occurs in approximately three to eight individuals per 100. In the same general U.S. and European population, homozygous factor V Leiden thrombophilia affects approximately one in 5,000 individuals. The frequency in African Americans, Asian Americans, Hispanic Americans and Native Americans is smaller than that of Caucasian Americans, but is still present at approximately 0.45-2% of individuals tested. Factor V Leiden thrombophilia is very rare in individuals who have only Asian, African, and indigenous Australian descent.

Signs and symptoms

The symptoms of factor V Leiden thrombophilia vary. Some affected individuals have no physical problems. Other individuals will have complications including blood clots blocking blood vessels (thromboembolism), deep vein thrombosis, unexplained multiple miscarriages and stillborn infants, gall bladder dysfunction, strokes, and heart attacks. The most common physical sign of factor V Leiden thrombophilia is thromboembolism (a blockage in the veins caused by a free floating clot [embolus]). Venous thromboembolism is most common in the deep veins of the legs (deep venous thrombosis or DVT of the legs). Since non-specific and common factor V Leiden thrombophilia are suspected in individuals who have had multiple blood clots in the veins (venous thrombosis), more than three unexplained miscarriages, or a family history of individuals with multiple blood clots in the blood vessels.

Diagnosis

Diagnosis of factor V Leiden thrombophilia can be done through a blood coagulation screening test or DNA analysis of the gene that codes for factor V.

The blood coagulation screening test uses the breakdown protein APC in a resistance study to see how quickly the factor V is broken down as compared to other blood clotting factors. An individual with factor V Leiden thrombophilia has factor V that is resistant or much slower to being broken down by the APC protein. At this time there are two types of APC resistance screening tests for factor V Leiden thrombophilia. The preferred test is the "modified second generation" APC resistance study because an extra step in the testing (dilution by plasma without factor V) makes it almost 100% accurate even in pregnant women and patients being treated by medications such as heparin and warfarin.

The DNA or molecular analysis examines the F5 gene to learn if the gene is altered or mutated.

Prenatal diagnosis is not offered routinely because the disorder is fairly mild and effective treatment is available.

Treatment and management

The treatment and management of individuals affected by factor V Leiden thrombophilia is focused on prevention of floating blood clots (thrombosis) and thromboembolism. The management of affected individuals should be overseen by a hematologist who specialized in blood clotting disorders and a general practitioner or internist who can work closely with the hematologist.

At different times of life, different specialists may need to be added. For example, when pregnant, a perinatologist or high-risk obstetrician should work with the hematologist during pregnancy. Additionally, individuals who have had a deep vein clot or stroke may need to consult a vascular specialist and/or neurologist.

The physicians managing an affected individual's care should discuss with them the timing, risks, and benefits of taking birth control pills and taking "blood thinning" anticoagulant medications like warfarin, aspirin, and heparin. Individuals affected by factor V Leiden thrombophilia should also be examined to make sure they do not have other blood clotting disorders in addition to factor V Leiden thrombophilia.

Prognosis

Individuals affected by factor V Leiden thrombophilia have a wide range of symptoms and signs. Some individuals affected by factor V Leiden thrombophilia will never develop physical signs and symptoms of the disorder. Other individuals will be more severely affected. Most affected individuals will not experience their first clotting event until adulthood. However, individuals with homozygous factor V Leiden thrombophilia have a significantly increased risk to have symptoms of the disease at a younger age. Treatment and close management of the disorder can reduce the risk of thromboembolism significantly.

Resources

PERIODICALS

Major, D. A., et al. "Cardiovascular Implications of the Factor V Leiden Mutation." American Heart Journal (August 2000): 189-195.

ORGANIZATIONS

Thrombophilia Support. <http://www.fvleiden.org>.

WEBSITES

"Factor V Leiden Thrombophilia." GeneClinics. <http://www.geneclinics.org/profiles/factor-v-leiden/index.html>.

Thrombophilia Support Page. <http://www.fvleiden.org>.

"Venous Thrombosis and Factor V (Leiden) Mutation." Genetic Drift Newletter 14 (Spring 1997). <http://www.mostgene.org>.

Dawn A. Jacob, MS, CGC