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Vol. 14: Spring, 1997 Molecular Genetic Testing in Mainstream Medicine |
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Vol. 14: Spring, 1997 Molecular Genetic Testing in Mainstream Medicine |
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.
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.
|
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.
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.
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.
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.
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.
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.
If the mutation is identified, it:
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.
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Sequence of clinical events and testing referrals:
This case illustrates:
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
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