Vol. 20: Fall 2002
Genetic Considerations in Thrombotic Disorders
Heterozygote Counseling for the
Factor V Leiden Mutation
Heterozygosity for the Leiden mutation in the factor V gene (FVL) is common and may present complex counseling issues. Heterozygosity refers to the situation when an individual has a single Leiden mutation in one of the factor V genes (see Adult Thrombotic Disorders in this issue of the Genetic Drift). It is inherited in an autosomal dominant manner, and may be identified in individuals with thrombosis or their family members. Heterozygotes exhibit reduced penetrance, meaning some individuals will never exhibit symptoms. In this condition, at least 90% of heterozygotes are asymptomatic throughout their lives. The heterozygote frequency is 5% of the Caucasian US population, 2% of Hispanic Americans, about 1% of African Americans and Native Americans, and less than 1% of Asian Americans. In the general population, deep vein thrombosis occurs in 1 in 1,000 individuals. Heterozygosity for FVL confers a 4-8-fold increased lifetime risk for deep vein thrombosis, yet thrombosis occurs with other circumstantial factors in 50% of cases. Twenty to sixty percent of Caucasians with thrombosis have FVL, and most of these are heterozygotes. Homozygotes, or those with two copies of the faulty gene, have up to an 80-fold risk for thrombosis. For genetic counseling of heterozygotes, it is useful to divide the asymptomatic from the symptomatic, and adults from children.
Asymptomatic adults should be informed of increased thrombotic risks with oral contraceptives and hormone replacement therapy, surgery, prolonged immobilization, and pregnancy, and puerperium. In addition, they may be tested for coexisiting abnormalities such as the prothrombin mutation 20210A variant, functional deficiencies in protein S, C, and antithrombin III, and hyperhomocystinemia, additional defects that significantly increase the risk of thrombosis. Prophylactic use of anticoagulants is not routine, but a short course may be used in the high-risk clinical settings listed above.Symptomatic adults with FVL who have had a thrombotic event are at a 2-4-fold risk of another event compared with the normal genotype. Testing them for additional risk factors such as those above is recommended and neatly outlined in the American College of Medical Genetics Consensus Statement on factor V Mutation Testing (see Grody et al. 2001). Treatment with anticoagulants is indicated, the duration determined on an individual basis. Women experiencing stillbirth, placental abruption, and severe pre-eclampsia may be heterozygotes exhibiting thrombophilic symptoms. Factor V Leiden is not known to be associated with arterial thrombosis.
Asymptomatic children are unlikely to have complications associated with heterozygosity. The majority who develop thrombosis have an additional genetic and/or environmental risk. Therefore, if heterozygosity is identified, further investigation of coexisting risks and parental counseling regarding risk and possible treatment during surgery and prolonged immobilization is indicated. However, there is no consensus on testing children for the mutation. Care should be taken with considering the issues involved with testing children, such as the benefit of timely medical benefit to the child versus the risk of stigmatization.
Families with FVL and an increased incidence of thrombosis appear to be predisposed to thrombosis beyond the magnitude generally associated with heterozygosity in the general population. Therefore, genetic counseling is frequently useful in evaluating individual risk, making recommendations for management, and addressing psychosocial issues.
References
Grody W, Griffin J, Taylor A, Korf B, Heit, J. (2001) American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing, Genetics in Medicine, 3:2, 139-147.Kujovich J, Goodnight S. (1999) GeneReviews: Factor V Leiden Thrombophilia, www.geneclinics.org
Position statements on testing children available through www.nsgc.org and www.ACMG.net
Ridker P, Miletich J, Hennekens C, Buring J. (1997) Ethnic Distribution of Factor V Leiden in 4047 Men and Women, JAMA, 227:16,1305-1307.
Contributed by Katherine Berry, MS, CGC (MT)
Genetic Considerations in Thrombotic Disorders
Table of Contents
Introduction
Adult Thrombotic Disorders
Pediatric Thrombotic Disorders
Fetal and Neonatal Effects of Maternal/Fetal Thrombotic Disorders
Teratogen Hot Topic: Anticoagulants
Heterozygote Counseling for Factor V Leiden mutation
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