Clinical Utility of Testing

Patients with Factor V Leiden (or another familial throm-bophilia) may present with one or more clinical pheno-types, including VTE, recurrent fetal loss, complications of pregnancy, and possibly arterial thrombosis.

VTE is a common disease, with an average annual incidence of over 1 per 1,000 person-years.20VTE is also a lethal disease, mostly due to pulmonary embolism. Almost one third of all pulmonary embolism patients die within 7 days, and one quarter die suddenly.20 For patients who die suddenly, available time is insufficient to recognize, diagnose, and begin therapy to alter the course of the disease. To improve survival and prevent complications, the incidence of VTE must be reduced, either by avoidance of high-risk exposures or by prophylaxis during such exposures. Independent clinical risk factors for VTE include confinement to a hospital (with or without surgery) or nursing home, trauma, malignant neoplasm (with or without chemotherapy), central venous catheterization, placement of a trans-venous pacemaker, prior superficial vein thrombosis, and serious neurologic disease with extremity paresis. Among women, additional risk factors include pregnancy and the puerperium, oral contraception, hormone (estrogen and/or progesterone) replacement therapy, and selective estrogen receptor modulator (SERM) therapy (e.g.,tamox-ifen, raloxifene). In addition to these risk factors, the patient age affects VTE risk, with a markedly increased risk with increased age for both men and women.20

While clinical risk factors can identify populations at risk, most persons that are exposed to such risk factors do not develop VTE. Moreover, about 25% of VTE patients have no obvious risk exposure.21 The discovery of APC-R and Factor V Leiden has provided new insights into the etiology of VTE. APC-R is the most commonly recognized familial thrombophilia among patients with VTE. The Factor V Leiden prevalence among incident VTE cases is 12% to 21%. Heterozygous Factor V Leiden carriers have an 8-fold increased risk for VTE, while the risk among homozygous carriers is increased 80- to 100-fold. VTE risk increases due to interaction between Factor V Leiden and other genetic disorders such as AT, PC, or PS deficiency. Genetic and clinical risk factors also interact to compound the risk of VTE. For example, VTE risk increases 30-fold among heterozygous Factor V Leiden women carriers receiving oral contraceptives, 7- to 16-fold during pregnancy or the puerperium, and 13- to 15-fold for postmenopausal women carriers receiving estrogen replacement therapy.22 Factor V Leiden carriers also may be at increased risk for VTE after surgery. The incidence of VTE among Factor V Leiden carriers also varies by age, ranging from 2 to 3 per 1,000 person-years for ages 15 to 30 years, to 7 to 11 per 1,000 person-years for age 60 years and older. However, compared to that for patients with AT, PC, or PS deficiency, the lifetime probability of developing VTE is considerably less for Factor V Leiden heterozygotes. Only 2.4% of Factor V Leiden carriers develop thrombosis by age 65 years.23 Thus, the vast majority of Factor V Leiden heterozygotes do not develop symptomatic VTE.

During counseling of patients or family members, it is most useful to estimate the incidence of VTE by age and exposure. For example, the incidence of VTE among women of childbearing age is about 1 per 10,000 woman-years.24 The risk for women of childbearing age is increased about 3-fold (e.g., to an incidence of 3 per 10,000 woman-years) among women taking oral contraceptives. The incidence of VTE among women who are heterozygous for Factor V Leiden in this age group is about 6 per 10,000 woman-years (e.g., a relative risk of 6 compared to women noncarriers), and that incidence is increased to about 30 per 10,000 woman-years for heterozygotes taking oral contraceptives. While this represents a 30-fold increased relative risk, the incidence is still only 0.3% per year (i.e., 99.7% of carriers on oral contraceptives will not develop VTE during that year). Only the patient can decide whether this risk is acceptable.

VTE also recurs frequently, with an estimated cumulative recurrence of 30% by 10 year.20 Independent predictors of recurrence include older age, obesity, malignant neoplasm, and extremity paresis. The risk of recurrent VTE is increased approximately 10-fold for patents with VTE and deficiency of AT, PC, or PS. While about 50% of patients with VTE are Factor V Leiden heterozygotes, there are conflicting data as to whether Factor V Leiden heterozygotes are at a higher risk for recurrent VTE compared to individuals who do not have Factor V Leiden.22 However, the risk of recurrence is significantly increased for Factor V Leiden patients who also are heterozygous for the prothrombin 20210G^A gene mutation (relative risk, 2.6 to 9.1), particularly for individuals without other clinical risk factors (relative risk, 5.1 or 4.0). The risk of recurrent VTE is 3-fold higher for individuals who are homozygous for Factor V Leiden.

Factor V Leiden also is a mild risk factor for recurrent pregnancy loss and possibly other serious obstetrical com plications (e.g., preeclampsia, fetal growth retardation, and placental abruption), possibly due to thrombosis of placental vessels and impaired placental perfusion.22

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