Factor V Leiden (Activated Protein C Resistance)

Factor V (five) Leiden (lye–den) is the name of a common genetic disorder that causes an increased risk of excessive blood clotting, known as thrombosis.

Factor V is one of the blood clotting factors or proteins produced by the liver. Normally, it circulates in the blood stream as an inactive substance. When it becomes activated, it contributes to the formation of a blood clot and is then switched off again by another clotting factor that helps to limit clotting to the area of injury, protein C.

In the case of factor V Leiden, there is a small abnormality in the factor V structure, causing it to be more resistant than normal to inactivation by protein C. This leads to more active factor V for a longer period of time and may result in excessive clotting. This abnormality is due to a single “substitution” in the gene for factor V. The affected gene may be passed through a family from a parent to children and is called the factor V Leiden mutation. The disorder is also known as “resistance to activated protein C.” The factor V Leiden mutation was discovered in 1993, and has since been found to be a very common cause of thrombosis in the Caucasian population. It is rare in African–Americans, Hispanics and Asians.

Thrombosis can occur in arteries and veins. Arteries are tough, elasticized blood vessels that carry blood away from the heart and deliver oxygen to the body. Thrombosis in an artery causes stroke, heart attack or damage to limbs or other organs, depending on the area of the arterial circulation affected. Other common contributing causes of arterial thrombosis are cigarette smoking, high blood pressure, high cholesterol and diabetes.

Veins are thinner, collapsible blood vessels that carry blood back from the tissues to the heart. It is estimated that from 500,000 – 2 million Americans experience a venous blood clot in their legs every year. These blood clots are often associated with surgery, pregnancy, birth control pills or other external factors.

Medical researchers estimate that 3 to 5 out of every 100 white Americans has one copy of the factor V Leiden mutation. Having one copy of this is referred to as being heterozygous. This means that these people have inherited the factor V Leiden gene from one parent and a normal gene from the other parent. The factor V Leiden gene is “dominant,” which means that it is not suppressed by the normal gene, although the normal gene does dilute its effect.

One person in 1,000 is homozygous for the mutation, which means that person has inherited the abnormal gene from both parents. Homozygous–affected individuals are much more likely to experience an episode of thrombosis than someone who is heterozygous. A person heterozygous for the mutation is 10 times more likely to develop a venous (vein–involved) blood clot than an unaffected person. Factor V Leiden probably increases the risk of arterial clots as well, but has a much stronger connection with venous blood clots, especially in the veins of the legs. Most blood clots in a heterozygous individual occur in association with some external cause. In women, the most common causes are pregnancy, birth control pills and hormone replacement after menopause. This is because the balance of coagulation is tipped towards clotting during pregnancy. Hormonal replacement and birth control pills mimic the same situation. In one study from Europe, 60% of the women who had blood clots during pregnancy turned out to have factor V Leiden. The risk of blood clots is actually highest during the 6 to 8 weeks after the birth of a baby. In men with factor V Leiden, blood clots may occur after surgery or an injury, especially an injury to the legs. Not everyone with factor V Leiden will develop a blood clot. Therefore, for some people with factor V Leiden there is no history of blood clotting in their parents, even if one of their parents has the gene.

A person who has inherited the gene from both parents (homozygous) has no normal factor V gene and is 40 times more likely than an unaffected person to develop a blood clot. Also, homozygous individuals can develop blood clots for no apparent external reason, which is called spontaneous thrombosis.

Symptoms

The symptoms of factor V Leiden include but are not limited to deep vein thrombosis (DVT) often in the lower extremities, pulmonary embolism, superficial thrombophlebitis, and recurrent pregnancy loss. Anyone with these symptoms should have an evaluation for the possibility of an underlying abnormality such as actor V Leiden. Following is an overview of these symptoms.

Deep vein thrombosis (DVT):

DVT is a condition in which blood clots form in the deep blood vessels, usually in the legs and groin. These blood clots can block the normal flow of blood returning from the legs to the heart. The main symptoms of DVT include pain and swelling. The pain may be sharp and sudden in onset or develop more gradually. The pain may be dull and throbbing. There may or may not be some swelling, redness and warmth over the area of the clot. Some people with a DVT may not have any symptoms.

Pulmonary embolism (PE):

PE occurs when a piece or all of a blood clot breaks off and is carried by the bloodstream to the lung. This clot will block the blood vessel in the lung. The size of the clot and the site of the obstruction of blood flow in the vessel will determine the size and severity of the pulmonary embolus. The symptoms of a PE may include difficulty breathing, rapid breathing, fast heartbeat and chest pain – especially when inhaling. Some patients only notice a dull ache in their chest and have fatigue or a feeling of anxiety. A few patients have no symptoms.

Superficial thrombophlebitis:

Superficial thrombophlebitis occurs when blood clots form in veins closer to the surface of the skin and is associated with inflammation. These clots may cause pain and irritation, and may also partially block blood flow in affected veins. Symptoms include: a hard, red vein which is often visible and commonly occurs in the legs or arms; the area may be warm and tender; the surrounding tissue may become itchy and swollen; there may be a throbbing or burning sensation beneath the skin’s surface; an associated fever is possible; and there may be difficulty sleeping as the pain worsens.

Pregnancy loss:

There is an increased risk of pregnancy loss in those who are either homozygous or heterozygous for the factor V Leiden mutation. Homozygous individuals have a greater risk for fetal loss and stillbirth than those who are heterozygous for this abnormality. One reason this may occur is excessive and abnormal clotting in the small blood vessels of the placenta. Also, there may be a greater risk of miscarriage if the baby and the mother are affected with the factor V Leiden mutation.

Treatment of Blood Clots

Once a patient is diagnosed with a blood clot, medications – anticoagulants – will be used to decrease the ability of the blood to clot. These anticoagulants may include:

Unfractionated heparin (UH) is usually administered in the hospital as an intravenous drug (directly into the vein). UH works though its interaction with a naturally occurring clotting factor, antithrombin III, that is important in limiting the propagation or growth of a clot. UH does not dissolve the blood clot, but it prevents further clot formation while the body’s natural mechanisms dissolve the clot. UH is usually used during the earliest phase of treatment. It requires frequent monitoring with blood tests as often as every 4 to 6 hours to ensure the correct effect is achieved. After the acute phase has passed, many patients may be changed over to low molecular weight heparin or Coumadin for their continued anticoagulation treatment.

Low molecular weight heparin (LMWH), which includes drugs such as Lovenox¨ and Innohep¨, is used for both the treatment and prevention of blood clots. LMWH is used commonly during pregnancy for the prevention of thrombotic complications. It may also be used for the initial treatment of blood clots and while a patient is being started on an oral anticoagulant such as Coumadin. LMWH is given by an injection under the skin much the same way diabetics take insulin. One or two injections per day may be prescribed. Laboratory monitoring of blood levels is not always required.

Coumadin (also known as warfarin) is usually administered by mouth in tablet form. It decreases blood clotting by blocking the effects of the vitamin K pathway in the liver. (Green leafy vegetables contain vitamin K.) This pathway is important in the production of some clotting factors that are able to help form a clot. Interference in this pathway will lead to a decreased amount of clotting factors able to form a clot, leading to anticoagulation or thinning of the blood. Each person may require a different dose of Coumadin, so frequent monitoring initially may be required to ensure that the Coumadin dose is safe and effective. A person being started on Coumadin will need to take some form of heparin for a period of time until the effect of the Coumadin has been proven to be consistently in the desired range. Please note that Coumadin should not be used during pregnancy.

After a deep vein thrombosis, a person will often be treated with an anticoagulant such as Coumadin for approximately 6 months. The total duration of treatment for a blood clot will depend on the cause and severity of the clot, identified underlying risk factors such as factor V Leiden, and will need to be decided on an individual basis.

Concluding Remark

Factor V Leiden is a lifelong disorder. However, not all affected individuals require lifelong anticoagulation therapy. For more information on factor V Leiden, please consult with your medical care provider.