Vol. 14, Spring 1997
Molecular Genetic Testing in Mainstream Medicine
Venous Thrombosis and the
Factor V (Leiden) Mutation
- Introduction
- Who should be tested?
- Deep vein thrombosis and pulmonary embolism
- The factor V mutation and APC resistance
- The factor V mutation test
- Prevalence of the factor V mutation and its effect on incidence of thrombosis
- Factor V mutation in women's health
- Diagnostic work-up of patients with inherited thrombosis
- How do patients benefit from factor V mutation testing?
- Managment of factor V heterozygotes and homozygotes
- Illustrative case report
- Introduction
The factor V mutation (factor V Leiden) is the most common genetic cause of venous thrombosis. It is involved in 20-40% of cases and is present in 3% of the general population. The mutation causes resistance to activated protein C (APC), and this induces a defect in the natural anticoagulation system. The other major genetic causes of venous thrombosis (deficiencies of protein C, protein S and antithrombin III) together account for only 5-10% of cases. Presence of the factor V mutation increases risk for venous thrombosis 7-fold in heterozygotes and 80-fold in homozygotes. This risk is increased still further in situations such as pregnancy, oral contraceptive use, estrogen therapy, malignancy, diabetes mellitus, immobilization or surgery. Ten percent of heterozygotes and almost all homozygotes experience venous thrombosis in their lifetime. The discovery of the factor V mutation in 1994 has revolutionized the diagnostic work-up of patients with hypercoagulability, and the ability to detect this mutation in asymptomatic relatives offers the opportunity to prevent venous thrombosis through special management of those at risk.
- Who should be tested? Indications include:
- Venous thrombosis or pulmonary embolism
- Transient ischemic attacks or premature stroke
- Peripheral vascular disease, particularly lower extremity occlusive disease
- History of a thrombotic event
- Family history of thrombosis or known factor V mutation in a relative
- 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
- Deep vein thrombosis and pulmonary embolism
Venous thrombosis and pulmonary embolism pose a serious health problem. In this country half a million people are hospitalized each year and 50,000-100,000 deaths occur due to venous thrombosis which is also a leading cause of maternal death. The incidence of symptomatic venous thrombosis cases is approximately 1 in 1000 people per year.
Venous thrombosis is a multifactorial condition caused by a combination of genetic, aquired or environmental influences. Natural anticoagulant systems (the protein C system and antithrombin III) are in place to keep coagulation in check. Excess clotting occurs when there is a disturbance in one of the coagulation inhibitor mechanisms or in natural lysis of clots.
- Known genetic causes explain about 50% of venous thrombosis cases. Most inherited thrombosis disorders involve a defect in one of the natural anticoagulant mechanisms.
Genetic
Disorder
|
Prevalence among patients
with venous thrombosis |
| Factor V mutation (APC resistance) |
20-40% |
| Protein S deficiency |
5-6% |
| Protein C deficiency |
2-5% |
| Antithrombin III deficiency |
2-4% |
| Plasminogen deficiency |
1-2% |
| Heparin cofactor II deficiency |
<1% |
| Unknown genetic defects |
~40% |
The most common genetic causes (APC resistance and deficiencies of protein C, protein S and antithrombin III) all have dominant inheritance with incomplete penetrance. Clinical presentation of thrombosis in affected individuals is similar for all the disorders and the thrombosis is often recurrent. In those affected, the first thrombotic event usually occurs in adulthood except for homozygous protein C deficiency which can cause severe thrombosis in the newborn. Studies have shown that up to a third of families affected with inherited thrombosis have two genetic defects, one of which is the factor V mutation. The factor V mutation has been discovered in numerous families with deficiencies in protein C, protein S or antithrombin III. This combination of two genetic risk factors (or homozygosity for one) increases penetrance dramatically, resulting in very high risk of thrombosis.
- Acquired or environmental conditions can precipitate a thrombotic event. These include:
- Pregnancy
- Oral contraceptive use
- Estrogen therapy
- Obesity
- Malignancy
- Diabetes mellitus
- Venous stasis from immobility
- Trauma
- Post-operative state
- Lupus anticoagulant
- The factor V mutation and APC resistance
Activated protein C (APC) is a component of the anticoagulant system which functions by inactivating, through cleavage, factors V and VIII in the coagulation cascade. APC resistance occurs when there is a poor anticoagulant response to APC. The factor V mutation (Leiden) is the cause of over 95% of APC resistance cases. This mutation is a single G to A base change that results in replacement of an arginine with a glutamine in the protein, destroying a cleavage site and thereby limiting factor V degradation by APC.
- The factor V mutation test
Testing for the factor V mutation involves polymerase chain reaction (PCR) amplification followed by detection of the single base change through restriction enzyme digestion and gel electrophoresis. The test determines presence or absence of the mutation and distinguishes between the heterozygous and homozygous genotype. Accuracy is >99%. The test can be performed rapidly, with results available in 1-2 days.
- Prevalence of the factor V mutation and its effect on incidence of thrombosis
The factor V mutation is very common in the general population. Studies of Caucasians have shown that 2-7% are heterozygotes and about 0.1% are homozygotes. Almost all factor V mutation homozygotes and about 10% of heterozygotes experience at least one thrombotic event during their lifetime. Thrombosis incidence is increased 7-fold in heterozygotes and 80-fold in homozygotes compared to incidence in people without the mutation. The risk is still higher when clinical or environmental risk conditions are also present. In addition, the risk of recurrent thromboic events is significantly higher in carriers of the factor V mutation than in patients without this abnormality.
- Factor V mutation in women's health
Pregnancy, oral contraceptive use and estrogen replacement therapy are all risk factors for thrombosis, and they increase risk significantly when coupled with a genetic hypercoagulability defect. Research also indicates that there may be an association between the factor V mutation and second trimester pregnancy loss. It has recently been shown that 60% of women who develop thrombosis during pregnancy or the postpartum period have the factor V mutation. It is standard practice for women with a history of thrombosis to receive thromboprophylaxis during pregnancy. Now it is suggested that factor V homozygotes and heterozygotes receive heparin treatment during pregnancy, regardless of whether they have previously experienced thrombosis. Factor V mutation testing should be performed before prescription of oral contraceptives if there is a personal or family history of thrombosis. Heterozygotes should receive counseling about their increased risk when taking oral contraceptives (35-fold greater than non-users of oral contraceptives who do not have the mutation) and all homozygotes should discontinue oral contraceptive use.
- Diagnostic work-up of patients with inherited thrombosis
After a few purely acquired causes of thrombosis have been ruled out (eg. vasculitis, lupus anticoagulant), the diagnostic workup of all thrombotic patients should include the factor V mutation test along with an "inherited hypercoagulability" panel. Diagnosis of an inherited thrombotic disorder can be made in approximately 50% of all venous thrombosis cases. The factor V mutation test is accurate regardless of the clinical condition or medication of the patient.
- How do patients benefit from factor V mutation testing?
If the mutation is identified, it:
- Establishes an etiology for an individual's thrombosis
- Identifies individuals and families at increased risk for future thrombosis
- Can contribute towards prevention of thrombosis by influencing patient management (for example, avoidance of oral contraceptives for individuals with the factor mutation and aggressive anticoagulant therapy after major surgery)
- Management of factor V heterozygotes and homozygotes
It has been recommended that a) homozygotes, with or without a history of thrombosis, receive preventive therapy during at-risk situations and extended anticoagulant therapy after a thrombotic event and b) heterozygotes with a history of thrombosis be treated like patients with a history of thrombosis due to deficiencies of protein C, protein S or antithrombin III and c) heterozygotes without personal or family histories of thrombosis be given prophylactic anticoagulant therapy in situations known to provoke thrombosis. Anyone found to have a factor V mutation should be counseled about secondary risk situations and relatives should be offered testing.
- Illustrative Case Report
Sequence of clinical events and testing referrals:
- II-1 had pulmonary embolism several years ago and standard tests for hypercoagulability (including protein C, protein S and antithrombin III deficiency) showed no abnormalities.
- I-1 had deep vein thrombosis (DVT) in 1995 after breaking a leg. Factor V mutation testing revealed he is a heterozygote.
- Subsequent testing showed that II-1 is homozygous for the factor V mutation, I-2 and II-3 are heterozygotes, and II-2 has a normal genotype. I-2 and II-3 have no personal history of DVT.
- II-3 became pregnant shortly after learning she was a heterozygote. She was treated with heparin throughout her pregnancy as a preventive measure against DVT.
This case illustrates:
- Use of the factor V mutation test towards prevention of venous thrombosis
- Though at increased risk, not all individuals with a factor V mutation experience thrombosis
- Oral contraceptives can trigger venous thrombosis in predisposed individuals
Contributed by Annette K. Taylor, PhD (CO)
The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131
Table of Contents:
Molecular Genetic Testing in Mainstream Medicine
Introduction
Venous Thrombosis and the Factor V (Leiden) Mutation
DNA Testing for Hereditary Hemochromatosis
APO E Genotype Testing for Broad Beta Disease (Type III Hyperlipoproteinemia)
Fetal Rh Testing for Maternal-Fetal Incompatibility
Type 1 (insulin-dependent) Diabetes Mellitus
Adult Onset Neurodegenerative Disorders: CAG Triplet Repeat Expansion Mutations
Genetic Testing for Prader-Willi and Angelman Syndromes
Clinical and Applied Molecular Genetics Laboratories - MoSt GeNe Region
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