Inherited Venous Thrombosis:

Factor V Leiden

Prothrombin (Factor II) Testing

About 50% of cases of venous thrombosis (clotting of the venous blood) are attributable to known genetic risk factors for hypercoagulability. The two most common of these are the factor V Leiden mutation and the prothrombin (factor II) mutation, followed in frequency by deficiencies of protein S, protein C and antithrombin. Identification of individuals with a genetic predisposition for hypercoagulability creates an opportunity for the prevention of a serious health problem.

What is the Factor V (Leiden) Mutation?
The factor V mutation is the most common cause of venous thrombosis, accounting for 20-40% of cases. This mutation is found in 4-6% of the U.S. population. It is relatively common in Caucasians and notably uncommon in Asian and African populations. The factor V mutation causes resistance to activated protein C (APC), which is responsible for preventing excess coagulation of blood. When individuals are resistant to APC because of the mutation, they are at risk for blood clots.

What is the Prothrombin Mutation?
The prothrombin mutation is the second most common genetic cause of venous thrombosis, accounting for 6-8% of venous thrombosis cases, and is also involved in certain arterial thrombotic conditions. This mutation is found in 1-3% of the U.S. population. The prothrombin mutation causes elevated levels of prothrombin in the blood. Prothrombin is involved in blood clotting; therefore elevated levels of prothrombin cause excessive clotting of the blood (thrombosis).

What are the Most Common Features of Factor V Leiden and Prothrombin Mutations?
Individuals with factor V or prothrombin mutations have a greater chance for experiencing venous thrombosis, peripheral vascular disease, stroke, recurrent miscarriages, pulmonary embolism (blood clot within an artery of the lung), and heart attack. Presence of the factor V mutation increases the risk for venous thrombosis 7-fold in heterozygotes (people carrying one copy of the mutation) and 80-fold in homozygotes (people carrying 2 copies of the mutation). The prothrombin mutation increases the risk for venous thrombosis 3 to 6-fold in heterozygotes and dramatically (the exact number is undetermined) in homozygotes. Certain situations and conditions increase the risk further; including pregnancy, obesity, malignancy, trauma, lupus anticoagulant, oral contraceptive use, surgery, estrogen therapy, diabetes mellitus, immobilization, and the presence of other defects in the coagulation pathway.

How are the Factor V (Leiden) and Prothrombin Mutations Inherited?
These disorders have autosomal dominant inheritance with reduced penetrance. Autosomal means the gene is not carried on a sex chromosome, and dominant means the inheritance of only one abnormal gene is needed to cause the disorder. These disorders have reduced penetrance because not everyone who carries the mutations experiences health complications. Ten percent of heterozygotes and almost all homozygotes with the factor V mutation experience venous thrombosis in their lifetime.

An individual who is heterozygous for a mutation has a 50% risk of passing the mutation to each of his/her children. The chance for a homozygous individual to pass a mutation to his/her children is 100%.

How is Testing for Venous Thrombosis Performed?
Factor V Leiden and Prothrombin DNA analysis is available for individuals who present with venous thrombosis or other indications for hypercoagulability testing (see indications below). A DNA blood test can detect the mutations within the factor V and prothrombin genes and can distinguish between heterozygotes and homozygotes. The test has an accuracy of greater than 99%. Among factor V Leiden heterozygotes with venous thrombosis, 10-12% also have the prothrombin mutation. Testing for mutations in the factor V and prothrombin genes detects the majority of cases of hypercoagulability caused by genetic defects.

The average age of onset of thrombosis is between the second and third decades; therefore, testing for at risk individuals should be performed prior to this time. The benefit of testing is to allow for proper management; including avoidance of aggravating factors, such as oral contraceptives, and aggressive anticoagulant therapy after major surgery.

• Venous thrombosis or pulmonary embolism

• Transient ischemic attacks (obstruction of a blood vessel) or premature stroke

• Peripheral vascular disease, particularly lower extremity occlusive disease

• Cerebral sinus thrombosis (clotting of the venous blood in the brain)

• History of a thrombotic event

• Family history of thrombosis or relative known to have a genetic mutation

• Prior to major surgery, pregnancy, postpartum, oral contraceptive use or estrogen therapy if there is a personal or family history of thrombosis

• Previous finding of activated protein C resistance by laboratory analysis (Factor V mutation)

• Premature myocardial infarction (heart attack) in women (prothrombin mutation)

• Multiple spontaneous abortions

■ Factor V Leiden DNA Test or Prothrombin DNA Test

    Specimen: 5 ml whole blood in a lavender top EDTA tube. Results available: 3 days

■ Combined Factor V Leiden/Prothrombin DNA Test

    Specimen: 5 ml whole blood in a lavender top EDTA tube. Results available: 3-4 days

■ Inherited Hypercoagulability Panels

Panel A: for patients not on Coumadin therapy Factor V Leiden DNA test, Prothrombin DNA test, Antithrombin Activity,              Protein C Activity, and Protein S Activity

Panel B: for patients on Coumadin Therapy Factor V Leiden DNA test, Prothrombin DNA test, Antithrombin Activity, Protein C Antigen, Protein S Antigen, Protein C/Factor IX Antigen Ratio, and Protein S Antigen/Factor IX Antigen Ratio 

Specimen: 5 ml whole blood in lavender top EDTA tube and 3 ml frozen plasma in yellow top citrate tubes in 1 ml aliquots. Draw specimen on Mon-Wed.  

Results available: 5-6 days (Panel A); 6-7 days (Panel B)

■ Note: any of these tests may also be ordered individually.

How Can Hypercoagulability Testint Be Arranged?
Physicians or healthcare providers may contact one of our Centers for consultations. Blood specimens may be sent by a physician or healthcare provider, or drawn at GeneCare if testing is recommended.

Individuals who are concerned about the risk of carrying a hypercoagulability mutation are encouraged to discuss genetic testing with their physicians and to consider having genetic counseling at GeneCare. During counseling, a detailed family history will be reviewed and appropriate testing determined for each individual situation.

Specimen Collection:

■ Fax DNA Consent Form, Laboratory Request, and family history to GeneCare for purposes of billing and reporting of results.

■ Chapel Hill, NC Fax: 919-967-9519

■ Rockville, MD Fax: 301-881-2596

■ Label each specimen tube with patient name, birth date, and collection date.

Specimen Transport:

■ Enclose Laboratory Request/Consent Forms

■ SHIP AT ROOM TEMPERATURE in kit to: GeneCare in Chapel Hill, NC.

DNA Specimens: 5 ml whole blood in a lavender top EDTA tube. Draw specimen Mon – Wed. Ship at room temperature.

Protein Specimens: Draw red top to remove tissue fluid contamination and discard. Draw 30ml blood in blue top 5-7ml sodium citrate (0.109 or 0.129M) tubes. Invert tubes. Spin 10 min. at 2000-3200 rev./min. to separate plasma. Using plastic pipettes, transfer 2ml plasma into 2ml plastic tubes, freeze ASAP. Send 3 tubes (6ml) priority overnight on minimum 5lbs dry ice directly to GeneCare. Keep frozen 6ml plasma for back up.

■ DHL/Airborne (800) 247-2676 priority overnight (or by our courier) to reach Kimball Genetics Monday-Thursday. Delivery required within 24 hours.

■ Notify GeneCare of shipment date and DHL/Airborne airbill tracking number.

Bertina, RM and Rosendaal, FR. Venous thrombosis -the interaction of genes and environment. N Engl J Med 1998; 338:1840-1841.

Francis, JL. Laboratory investigation of hypercoagulability. Semin Thromb Haemost 1998; 24: 111-126.

Makris, M. et al. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-1429.

Poort, SR et al. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-3703.

Rosendaal, FR et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 504-1508.

Simoni, P. et al. The risk of recurrent venous thromboembolism in patients with an Arg⁵⁰⁶àGln mutation in the gene for factor V (Factor V Leiden). N Engl J Med 1997; 336: 399-403.

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Last modified: May 25, 2004 04:26 PM
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