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Factor V Leiden

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    Factor V Leiden is a genetically acquired trait that can result in a thrombophilic (hypercoaguable) state resulting in the phenomenon of activated protein C resistance (APCR) as described below. Associated with factor V Leiden, APCR was first described in 1993; factor V Leiden was subsequently discovered in 1994. Over 95% of patients with APCR have factor V Leiden. Factor V Leiden's overall impact on the coagulation cascade described below.

    Mechanism of Action of Factor V Leiden:
    Factor V Leiden is characterized by a phenomenon called APCR where a genetic mutation in the factor V gene causes a change in the factor V protein making it resistant to inactivation by protein C.

    A detailed description of the clotting process is found on the clotting information web page. The function of protein C is to inactivate factor Va and factor VIIIa (the 'a' denotes the active form). The first step in this process is the activation of thrombomodulin by thrombin. Subsequently, protein C combines with thrombomodulin in order to produce activated Protein C (see Figure 1). Activated protein C then combines with protein S on the surface of a platelet (platelets are the clotting cells that circulate in the blood and provide phospholipids to support that clotting process). Activated protein C can then degrade factor Va and factor VIIIa (see Figure 2). When one has factor V Leiden, the factor Va is resistant to the normal effects of activated protein C, thus the term activated protein C resistance. The result is that factor V Leiden is inactivated by activated protein C at a much slower rate (see Figure 3), thus leading to a thrombophilic (propensity to clot) state by having increased activity of factor V in the blood.

    Epidemiology of Factor V Leiden:
    Factor V Leiden is seen more commonly in the northern European populations. About 4-7% of the general population is heterozygous (see * below) for factor V Leiden. About 0.06 to 0.25% of the population is homozygous (see * below) for factor V Leiden. The factor V Leiden mutation is relatively uncommon in the native populations of Asia, Africa and North America. In contrast, in Greece and southern Sweden, rates above 10% have been reported.

    Risks of Factor V Leiden:
    The overall estimated incidence (annual occurrence) of deep venous thrombosis is 1 episode for every 1000 persons. This figure does not separate patients who had predisposing conditions from those who do not.

    At this time, the data available do not suggest any role between factor V Leiden and arterial thrombosis (stroke, heart attack).

    The role of factor V Leiden and venous thromboembolic disease is shown in the table below. The table shows the increase in risk compared with a patient without a known thrombophilic state. Relative risk is a numerical representation of the effects of a condition or treatment on an individual. If a condition or treatment has a relative risk of 1, patients with the condition have no additional risk or benefit from those without the condition. In the studies used below, a relative risk greater than 1 shows an increased risk. For the table below, a relative risk of 4 means that individuals with that condition are 4 times as likely as similar individuals without the same condition, to develop a venous thrombotic event. Despite the increased risk, it is important to remember that the relative risk is a statistical tool to help guide clinicians and scientists and that individual persons can have increased or decreased risks. Even with a very high relative risk, there is no guarantee that a venous thrombotic event will occur.

    Treatment of Factor V Leiden:
    Treatment of a patient with factor V Leiden depends upon the individual patient's risk of recurrent thromboembolic disease. When one has a venous clot, regardless of what thrombophilic state(s) one may have, that person will receive anticoagulation. This is accomplished by several different medications: 1) heparin, 2) warfarin and 3) low-molecular-weight heparins. These medications are generally used for 3-6 months. Further continuation is generally not indicated in factor V Leiden heterozygotes after a single thromboembolic episode given the risk of bleeding associated with anticoagulation. Patients that have had multiple thromboembolic episodes or are at high risk of further episodes (for example, multiple deficiencies or factor V Leiden homozygotes) are likely started on long-term anticoagulation.

    The use of long-term anticoagulation has risks associated with it (approximately a 3% chance per year of having a major hemorrhage, of which approximately 1/5 are fatal). Beginning long-term anticoagulation is influenced by the patient's overall risk of recurrent thrombosis balanced against the risks associated with long-term anticoagulation on an individual basis.

    Further Information:
    For further information on the other thrombophilic states, please refer to their respective pages. Brief information on the various medications that are discussed above and are regularly used to treat clotting disorders is discussed on the medication pages. A selection of the references used to compile this information is listed on the references page.

    Thrombophilic Status
    Relative Risk of Venous Thrombosis
    Normal 1
    Oral contraceptive (OCP) use 4
    Factor V Leiden, heterozygous 5 to 7
    Factor V Leiden, heterozygous + OCP 30 to 35
    Factor V Leiden, homozygous 80
    Factor V Leiden, homozygous + OCP ??? >100
    Prothrombin Gene Mutation, heterozygous 3
    Prothrombin Gene Mutation, homozygous ??? possible risk of arterial thrombosis
    Prothrombin Gene Mutation, heterozygous + OCP 16
    Protein C deficiency, heterozygous 7
    Protein C deficiency, homozygous Severe thrombosis at birth
    Protein S deficiency, heterozygous 6
    Protein S deficiency, homozygous Severe thrombosis at birth
    Antithrombin deficiency, heterozygous 5
    Antithrombin deficiency, homozygous Thought to be lethal prior to birth
    Hyperhomocysteinemia 2 to 4
    Hyperhomocysteinemia combined with Factor V Leiden, heterozygous 20
    *The terms heterozygous (hetero-different) and homozygous (homo-same) are terms used in genetics. The human genome contains to copies of the information. If the copies are the same, they are homozygous; if the copies are different, they are heterozygous. For example, take a protein called A. The normal genome would code for the protein as AA. This is homozygous for the normal protein. If there is a variation of the protein called a, there are two possible ways to get the a. The genome could be Aa, which is called heterozygous or the genome could be aa, which is called homozygous.