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The Human Genome

My Sister had a Venous Thromboembolism. Will I?

John M. Quillin, MS, CGC; Joann N. Bodurtha, MD, MPH

A 28-year-old woman consults her physician about a pregnancy she is planning. Her sister died the prior year from a venous thromboembolism (VTE) during pregnancy. Will this patient also have a VTE? How should her doctor counsel her about pregnancy risks and risk management?

Venous thromboembolism, with an annual incidence of about 1 per 1,000, is a significant health problem.^1,2 The occurrence of VTE typically results from abnormal blood flow, blood vessel damage, and/or proteins in the clotting pathway resulting in thrombus formation that could be fatal.³ Venous thromboembolism is of particular concern for women who may have life events or make other choices that increase risk for blood clots such as using exogenous hormones (eg, oral contraceptives [OCs], hormone replacement therapy, and selective estrogen receptor modulators such as tamoxifen). These and other risk factors for VTE are summarized in Table 1.^4,5 With growing knowledge about familial risk for VTE, clinicians can be more patient-specific in their treatments and recommendations for these women.

Family is an independent risk factor for VTE.⁶ Known mutations in genes associated with blood clotting account for a significant proportion of VTE. Some of the currently known relevant genes are shown in Table 2. In particular, the factor V Leiden mutation confers resistance to activated protein C and accounts for about 20% of VTE.^7,8 There is increased risk for blood clots during pregnancy, and this risk may be higher with a positive family history.⁹ Conversely, increased risk for blood clots is linked to adverse pregnancy outcomes including miscarriage, stillbirth, preeclampsia, and intrauterine growth retardation.^10-13 An understanding of the inherited nature of susceptibility to blood clots can assist with informed decision-making and counseling patients about their risks.

The known inherited risk factors for VTE appear to be transmitted in a dominant manner. Heterozygotes (those with one mutated gene copy) have some increased risk, and homozygotes (those with two mutated gene copies) may have even higher risk. If both parents are heterozygotes for a susceptibility gene, each child has a 50% chance to be a heterozygote, and a 25% chance to be a homozygote (Figure 1). However, inheriting a mutation in one of these genes does not predict VTE with certainty. Heterozygotes for the factor V Leiden mutation have a risk of 3 to 5 per 1,000 for VTE¹⁴ and a lifetime chance of about 10%.¹⁵

Whether an individual woman will have a VTE depends on a combination of environmental and inherited risk factors. Increasing environmental (eg, smoking) or situational exposures such as OC use or pregnancy may be more likely to lead to VTE if an individual has inherited risk factors for VTE (Figure 2). Thus, while OC use may carry a 4-fold increased risk for VTE, risk is increased 35-fold with OC use among heterozygotes for factor V Leiden.¹⁶ There are also documented gene-gene interactions such as combined mutations in factor V and the prothrombin genes.¹⁷ Other genes may influence multiple proteins in the clotting pathway.¹⁸ In some cases, knowing a woman’s risk for VTE changes medical management. For instance, women at high risk will need to weigh the risks of VTE with OC use against the benefits of preventing unwanted pregnancy. High-risk women who are currently pregnant might consider anticoagulation therapy during pregnancy and postpartum.

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Screening for risk status is not necessarily helpful for the general population.⁵ Mass screening for factor V Leiden, for example, might identify 5 carriers for every 100 women screened. Most of these women will never experience a VTE,¹⁹ yet many might be advised against OC use. Furthermore, testing for genetic susceptibility could potentially lead to unwanted outcomes including employment or insurance discrimination. Although some organizations suggest that a formal written consent is not a requirement before testing for inherited thrombophilia,²⁰ many agree that a discussion of the pros and cons should precede any testing, especially for asymptomatic family members.⁵

Because of the complexity and uncertain benefits of mass screening, providers will need to be selective about whom to offer testing for thrombophilia, including those with risk factors that suggest inherited risk (eg, family history of VTE or known VTE-associated mutation, multiple unexplained miscarriages, or idiopathic or recurrent VTE). Thrombophilia testing has been incorporated into the mainstream of medical care, and many organizations including the American College of Medical Genetics (ACMG) do not suggest a formal written informed consent prior to testing.⁵ Still, patients should have the benefit of discussion of the limitations and implications of testing. Resources such as the American Venous Forum Web site (http://www.venous-info.com) or discussions with relevant specialists such as hematologists, perinatologists, or genetics professionals can facilitate informed decision-making. Providers can locate genetic counselors, for example, through the National Society of Genetic Counselors Web site (http://www.nsgc.org).

Knowing about one’s risk for VTE may be helpful for some women. Whether an individual woman will benefit from testing depends on her risk factors, life situation, and personal preferences. Providers can help patients by noting important risk factors, such as personal or family history of VTE, before beginning exogenous hormones and in preconceptional/prenatal counseling. By appreciating the complexity of inherited thrombophilia and tailoring care to individual susceptibilities, providers will optimize care for their patients.

John M. Quillin, MS, CGC, is genetic counselor, and Joann N. Bodurtha, MD, MPH, is professor of human genetics, pediatrics, and obstetrics and gynecology, both in the Department of Human Genetics, Virginia Commonwealth University, Richmond.

References

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