Course:MEDG550/Student Activities/Factor V Leiden Thrombophilia

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Description

Factor V Leiden thrombophilia is an inherited condition that affects blood clotting. Individuals with factor V Leiden thrombophilia are at an increased risk to develop a blood clot [1]. Individuals with factor V Leiden thrombophilia have an elevated risk over the general population to develop a specific type of blood clot called venous thromboembolism (VTE) [1], which are blood clots that form in the veins. The most common type of VTE is called deep vein thrombosis (DVT), which is when blood clots form in the deep veins, typically in the legs. Factor V Leiden thrombophilia also increases the risk for pulmonary embolism [1], which is when a clot breaks from its original site and travels through the bloodstream to the lungs. Blood clots are dangerous because they can block the flow of blood within the blood vessels. VTE can occur at any age in people with factor V Leiden thrombophilia, but if a VTE occurs before the age of 50 this may be suggestive of factor V Leiden thrombophilia [1][2]. Having factor V Leiden thrombophilia increases an individual’s risk for VTE, however only approximately 10% of people with the condition actually experience an episode of VTE [3].

Genetics

Gene

Genes are like instruction manuals in our cells, providing the guidance needed for our bodies develop and function the way they should. Gene mutations are changes or alterations in this instruction manual. These changes can affect how a gene works, and in some cases can lead to health conditions.

Factor V Leiden thrombophilia is caused by one specific mutation in the F5 gene. This is the only mutation known to cause factor V Leiden thrombophilia [1][4]. The F5 gene produces a protein called coagulation factor V, which helps normal blood clotting to occur. In individuals without the factor V Leiden mutation, another protein called activated protein C (APC) inactivates coagulation factor V, which stops the clotting process [5]. However in individuals with the factor V Leiden mutation, coagulation factor V cannot be inactivated by APC, and thus abnormal clotting can occur [1][4].

Inheritance

Autosomal dominant inheritance. When one partner has factor V Leiden thrombophilia (affected) there is a 50% chance they will pass down their normal copy (blue square) and a 50% chance they will pass down their copy with the mutation (white square) each time they have a child. This means there is a 50% chance for each of their children to have factor V Leiden thrombophilia.

Factor V Leiden thrombophilia is inherited in an autosomal dominant pattern [1]. Autosomal inheritance means that females and males are affected equally. A condition is considered dominant if only one copy of the mutation causes the health problem. All of the cells in an individual’s body contain two copies of the F5 gene, with one copy inherited from the mother and one copy inherited from the father. If one of those copies has the factor V Leiden mutation, the individual will have factor V Leiden thrombophilia. An individual with one factor V Leiden mutation has a 50% chance of passing down the copy of the gene with the mutation to each of his/her children. This is because the affected individual can either pass down their working copy, or their copy with the mutation, each time they have a child. However, as described in the next section, just because the child inherits the factor V Leiden mutation does not mean they will have an episode of VTE in their lifetime. Since the factor V Leiden mutation is common the in the European population, both parents may carry the mutation. In this case there is still a 50% chance for their child inherit one copy of the mutation. However, there is also a 25% chance the child will inherit two copies of the mutation, which results in a more severe form of factor V Leiden thrombophilia with a higher lifetime risk of developing VTE compared to those that have one mutation [6]. Lastly, if an individual has two copies of the factor V Leiden mutation, there is a 100% chance they will pass down one copy of the mutation to each of their children.

Risk for VTE

(A) An individual’s risk for developing VTE can be explained using this jar model. The jar represents one’s risk for having an episode of VTE, and VTE only develops when the jar becomes full. (B) Factor V Leiden mutation is one of many genetic factors that contributes to VTE risk. Two individuals with factor V Leiden thrombophilia can have different background risks based on the presence or absence of other genetic risk factors. (C) Environmental factors can contribute to an episode of VTE. A person with factor V Leiden thrombophilia may never have a “full jar”, and thus would never experience VTE.

Factor V Leiden thrombophilia is a genetic predisposing factor for VTE. This means it increases one’s risk for having an episode of VTE in their lifetime, but does not guarantee an episode because there are many other factors that contribute to clotting. Many individuals with factor V Leiden thrombophilia never experience VTE, and many individuals without factor V Leiden thrombophilia do experience VTE. The incidence of VTE in the general population is 1 in 1000 (0.1%) every year [7]. In individuals with one factor V Leiden mutation the chance of VTE increases approximately 5 times, which means the risk 5 in 1000 (0.5%) every year. Having two copies of the factor V Leiden mutation raises the risk for VTE to about 50 in 1000 (5%) [6]. The reason that factor V Leiden thrombophilia is considered a risk factor for VTE is because there are many components, both genetic and environmental that can affect blood clotting. The blood clotting process is complex and involves many different genes, and everybody likely has some genetic risk factors for VTE. Mutations in any of these genes can be considered risk factors for VTE, and the factor V Leiden mutation is just one of these factors [6]. Environmental risk factors that contribute to VTE include age, surgery, pregnancy, oral contraceptives, and immobility (such as a long flight) [1]. It is important to talk with your doctor if you have factor V Leiden thrombophilia and are or will experience any of these environmental factors, as they may impact your risk for VTE more than the general population [1]. Importantly, family history of VTE can help to determine risk. Individuals with factor V Leiden thrombophilia are at increased risk if they have a positive family history of VTE, compared to people with factor V Leiden thrombophilia without a family history of VTE. A positive family history suggests additional genetic risk factors may be present in the family [8].

Prevalence

The most common type of inherited thrombophilia is Factor V Leiden thrombophilia. It also accounts for 20-25% of all thrombotic events, caused by both inherited and non-inherited thrombophilia [6]. In people of European ethnicity, roughly 3-8% have one copy of the factor V Leiden mutation, and about 1 in 5000 people carry two copies of the mutation [1]. The factor V Leiden mutation is found at a lower frequency in individuals of other ancestral backgrounds, especially in people of Asian, African, and indigenous Australian ethnicity [1].

Diagnosis & Management

Diagnosis

Diagnosis of factor V Leiden thrombophilia is done using either the APC resistance assay or DNA analysis of the F5 gene [3]. Individuals who are diagnosed using the APC resistance assay should have DNA testing to determine if they carry one or two copies of the factor V Leiden mutation [3]. The following is a list of scenarios where testing for factor V Leiden thrombophilia is recommended by the American College of Medical Genetics [3]:

  • first VTE of unknown cause (at any age, but especially younger than 50 years)
  • personal history of recurrent VTE
  • venous thrombosis at uncommon sites (such as cerebral, mesenteric, portal and hepatic veins)
  • VTE during or within a few weeks following pregnancy
  • VTE while taking oral contraceptive pills or hormone replacement therapy
  • VTE in an individual with a first-degree family member who experienced VTE before the age of 50

Management

Treatment for factor V Leiden thrombophilia is only indicated if VTE develops. The first episode of VTE is treated according to the standard procedure, which involves short-term treatment with anticoagulation medications. Heparin is administered intravenously as well as short-term warfarin (except during pregnancy) [1]. The benefit of long-term use of anticoagulation medications is unproven for people with factor V Leiden thrombophilia. Life expectancy for individuals with one copy of the factor V Leiden mutation, who are not on long-term anticoagulation medications is the same as the general population [1]. Therefore, long-term oral anticoagulant medication is generally only considered for individuals with factor V Leiden thrombophilia who have recurrent VTE, coexisting thrombophilic disorders, coexisting environmental risk factors, or those with two factor V Leiden mutations [1].

Genetic Counselling

A genetic counsellor is a healthcare professional that is trained in both genetics and counselling. They work with individuals and families with genetic disorders such as factor V Leiden thrombophilia. During an appointment, a genetic counsellor will gather detailed medical and family histories. This information can be used to help individuals understand how a condition may be passed through their family and identify who in the family might be at risk of having the disease. Genetic counsellors are able to explain genetic testing options and are trained to help individuals decide if genetic testing is right for them, recognizing that this is a highly personal choice. They can provide information and education about the condition, and help connect individuals to resources, other care professionals, or support groups.

Psychosocial Considerations

A diagnosis with factor V Leiden thrombophilia may bring about a range of emotions, including anxiety and concern about potential health complications. Individuals may face challenges in making decisions about lifestyle, family planning, and medical interventions. The condition can also impact relationships, as family members may share concerns about inherited risks. Moreover, individuals with factor V Leiden thrombophilia may experience heightened stress related to the need for watchful monitoring and preventive measures to manage clotting risks. Talking with a genetic counsellor may help provide support to patients surrounding the emotional and social impacts of having factor V Leiden thrombophilia.

Additional Genetic Counselling Issues

Most of the information presented on this page can be discussed in further detail with a genetic counsellor. However, these are some additional considerations for the genetic counselling of factor V Leiden thrombophilia. Every individual has a chance to experience VTE in his/her lifetime, and this chance is determined by many risk factors, both environmental and genetic. It is currently not possible to determine all genetic risk factors in an individual or family, because we do not know of all of the genetic risk factors for thrombosis, and their relative contributions to risk. Since the factor V Leiden mutation is common in the European population, when one partner has factor V Leiden thrombophilia, DNA testing of an asymptomatic partner may be suggested in the preconception period in order to rule out the chance that a child could inherit two copies of the mutation [3]. However, F5 DNA testing of a fetus in the prenatal period is not recommended, as it will not contribute to a meaningful estimate of the risk of VTE later in the child’s life [3]. Testing of asymptomatic children is not recommended, since VTE is rarely experienced before young adulthood [1].

Patient resources

  1. Information for patients and families: https://www.stoptheclot.org/documents/FactorVLeiden-lw.pdf
  2. Journal article for patients: http://circ.ahajournals.org/content/107/15/e94.full
  3. Read Lori's story: https://www.stoptheclot.org/risk_factors/what_is_factor_v_leiden.htm

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 [Kujovich, J.L., Factor V Leiden thrombophilia. Genet Med, 2011. 13(1): p. 1-16].
  2. ↑ [Grody, W.W., et al., American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med, 2001. 3(2): p. 139-48.].
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 [Heit, J.A., et al., The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study. J Thromb Haemost, 2005. 3(2): p. 305-11.]
  4. ↑ 4.0 4.1 [Bertina, R.M., et al., Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature, 1994. 369(6475): p. 64-7.]
  5. ↑ [Dahlback, B., Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood, 2008. 112(1): p. 19-27.]
  6. ↑ 6.0 6.1 6.2 6.3 [Rosendaal, F.R. and P.H. Reitsma, Genetics of venous thrombosis. J Thromb Haemost, 2009. 7 Suppl 1: p. 301-4.]
  7. ↑ [Heit, J.A., et al., Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med, 2000. 160(6): p. 809-15.]
  8. ↑ [Bezemer, I.D., et al., The value of family history as a risk indicator for venous thrombosis. Arch Intern Med, 2009. 169(6): p. 610-5.]
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