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What is being tested?

Factor V (Leiden) and prothrombin are proteins in the liver and belong to a group of proteins, collectively known as coagulation factors - a series of proteins that are activated in a step by step process (called the coagulation cascade) when a blood vessel is injured. The end result of the coagulation cascade is a blood clot that creates a barrier over the injury site, protecting it until it heals.

Factor V (Leiden) is a variant form of Factor V that is caused by a genetic point mutation - a change in one of the nucleotides on the gene that guides the creation of Factor V protein. This altered protein activates normally to participate in stimulating blood coagulation, but it resists being degraded by activated Protein C (APC) - thus remaining active for longer than the normal Factor V protein. The result of this resistance is that clotting remains more active than usual, which leads to a higher risk of blood clot forming in the deep veins of legs (DVT) or breaking off and blocking a vein (venous thromboembolism or VTE).

During blood clotting, an enzyme converts prothrombin to thrombin. A mutation in the gene that codes for prothrombin, termed Prothrombin 20210 may lead to greater amounts of prothrombin and thus abnormal clotting and therefore a greater risk of DVT or VTE.

Prothrombin (PT) 20210 is a variant form prothrombin, also caused by a genetic point mutation. PT 20210 is also associated with an increased risk of VTE. This variant does not alter the activity or functional properties of prothrombin, rather it is responsible for the production of higher levels of prothrombin in those that carry the variant.

Factor V (Leiden) and PT 20210 are independent mutations that are inherited separately and tested at the same time. Testing of each is intended to identify whether or not the mutation is present and to determine whether the person has inherited one mutated gene copy (heterozygous) or may have inherited two mutated gene copies (homozygous).

How is it used?

Factor V mutation (Leiden) and prothrombin 20210 tests are ordered, together along with other tests related to hypercoagulability, to help screen for the underlying causes of venous thromboembolism. The most common reason is to investigate someone who has had a venous thrombosis and is both less than 50 years of age and comes from a family where two or more other family members have been affected. In this situation testing helps in decisions about whether to start anticoagulation therapy and how long it should continue.

Activated protein C (APC) resistance testing is done to screen for Factor V mutation (Leiden). About 95% of the time, those who have APC resistance will have a Factor V (Leiden) mutation. If resistance is present, then a test for the Factor V (Leiden) gene mutation is done, both to confirm the diagnosis and to determine whether the patient is heterozygous or homozygous for the mutation.

The PT 20210 mutation must be diagnosed with genetic testing, checking directly for the gene mutation, and determining whether the patient is heterozygous or homozygous. Although prothrombin levels are usually moderately elevated with this mutation and could be measured, they are not clinically useful in finding this mutation.

At this time, experts do not recommend screening the general population, testing in unselected patients presenting with venous thrombosis or their family members. If the mutation is present, then the person is at a very small increased risk for developing a blood clot, but there is variability in how the gene is actually expressed. Many of those who do have the mutation(s) will never have a VTE.

When is it requested?

PT 20210 and Factor V mutation (Leiden) tests are ordered when it is suspected that a patient has an inherited risk factor for blood clots, for instance when someone has:

  • A first venous thromboembolism (VTE) at a relatively young age (less than 50 years old).
  • Recurring DVT
  • A blood clot in an unsualy part of the body such as veins of the kidneys, brain, gut and pelvis, liver or in the eye
  • A first VTE related to oral contraceptive use, pregnancy or hormone replacement therapy
  • Unexplained miscarriages, especially when it occurs in the second or third trimester of pregnancy

In Australia, current expert advice is that testing of family members is rarely useful. Knowledge of whether a patient or family member has a Factor V mutation (Leiden) or PT 20210 gene mutation very rarely alters the management plan following diagnosis of a venous thromboembolic event and does not change the advice given to a patient regarding the risk of venous thromboembolic events after taking a careful history of previous thrombotic events and relevant family history.
Once APC Resistance testing, Factor V (Leiden) mutation testing, and PT 20210 gene mutation testing has been done it is usually not repeated unless there is a need for verification.

What does the result mean?

Resistance to activated Protein C is due to Factor V mutation (Leiden) 95% of the time, but if resistance is present the Factor V (Leiden) mutation should be confirmed with genetic testing.

Factor V mutation (Leiden) is the most common inherited clotting disorder. Its prevalence is increased in those of European descent, being present in about 4% of the Caucasian population. A patient with Factor V mutation (Leiden) may be heterozygous (has one copy of the changed gene and one normal gene) or homozygous (has two copies of the changed gene, this is more rare). Those that are heterozygous have about a 5-10% greater risk than normal of developing a venous thromboembolism (VTE), while those who are homozygous have a greater risk of thrombosis although this risk is still small.

If you have a single gene copy with the PT 20210 mutation, then you are heterozygous, if both copies are changed, then you are homozygous. Someone with a heterozygous or homozygous PT 20210 mutation will have a mild to moderate increase in their thrombin production, raising their risk of developing a VTE a small but significant amount. Although PT 20210 is less common than Factor V mutation (Leiden) (about 1-2% of the general population), it is also more prevalent in Caucasians than in those of other ethnic backgrounds.

Is there anything else I should know?

The risks that are associated with Factor V mutation (Leiden), PT 20210, and other inherited and acquired factor deficiencies that are thrombophilic (increase the risk of developing blood clots such as protein C and protein S deficiencies) are independent. You can have more than one of them and their associated risks are cumulative. Added to these inherited risks and acquired risks are controllable risk factors, such as oral contraceptive use, that may exacerbate the combined underlying risk factors. For instance, if you are heterozygous for Factor V mutation (Leiden), you may be at about a 10% greater than normal risk of developing a VTE. If you use oral contraceptives, that risk can jump to 35% higher than normal.

Factor V mutation (Leiden) and PT 20210 are genetic tests and as such you should have a detailed discussion with your doctor before agreeing to undertake the test. This discussion should include the reasons why the test is being recommended and how this will affect your medical management now and in the future.

Common questions

  • Should someone with a Factor V mutation (Leiden) be on long-term anticoagulant therapy?

Anticoagulant treatment is rarely influenced by the presence or absence of thrombophilic factors such as Factor V (Leiden). These rare situations might include co-inheritance with other thrombophilic factors or homozygous Factor V (Leiden) (both gene copies faulty). Factors influencing treatment decisions are complex and should be discussed with your doctor - ideally a haematologist specialising in coagulation abnormalities.

  • How is a VTE treated?

Regardless of the underlying cause, a VTE is usually treated with a short course of anticoagulants (often 3-6 months with a combination of heparin, warfarin and low-molecular weight heparins). At the end of this time period, the patient's risk level is assessed to see if further treatment is necessary. In very severe, recent-onset and life-threatening thrombosis, ‘clot-busting’ drugs called fibrinolytics (e.g. streptokinase or tPA) may be injected in hospital.

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