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Making the tough decisions on FVL

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January 2002
William Check, PhD

The American College of Medical Genetics published in March 2001 the first professional guidelines on factor V Leiden testing (www.acmg.net). Chair of the ACMG committee in charge was Wayne Grody, MD, PhD, professor in the departments of Pathology, Pediatrics, and Human Genetics at the University of California, Los Angeles, and director of UCLAMedical Center’s DNA diagnostic laboratory. "Our guidelines mostly coincide with the CAP recommendations," says Dr. Grody, who chairs the CAP’s Molecular Pathology Committee and CAP/ACMG Biochemical and Molecular Genetics Resource Committee.

Deciding who should be offered FVL testing generated considerable debate. Perhaps the entire U.S. population should be screened: The carrier rate is about seven percent in Caucasians and carriers are at five- to 10-fold increased risk of venous thromboembolism. "That sounds like a lot," Dr. Grody says, "but the baseline risk is very low, especially in younger adults." And what would you do for asymptomatic carriers? Anticoagulants carry a risk of bleeding that is higher than the risk of VTE. "In the end, we did not recommend population screening or prenatal or newborn screening," Dr. Grody says. The main indication for FVL testing remains unprovoked VTE in a person under the age of 50. The committee did not recommend testing relatives of persons who test positive, but they did not rule it out.

The other major consideration is women using oral contraceptives. A woman using OCs who is also an FVL carrier has a 35-fold increased risk of VTE. "It is surprising to many people that we did not recommend FVL testing in these women," Dr. Grody says. "I am still getting critical phone calls about it." The committee based its decision on a published study that calculated that 2.5 million women would need to be screened to prevent one death from VTE. In the process 90,000 carriers would be identified. If all 90,000 carriers selected less effective non-OC birth control, more would die of pregnancy complications than would die of the consequences of FVL.

Concomitant or followup screening tests were also debated, especially prothrombin G20210A, which has synergistic risk with FVL. UCLA hematologists said they prefer to order tests separately. But the ACMG committee recommended that patients positive for FVL be considered for other common thrombophilic factors with a similar phenotype for which testing is easy and available. "At this point, only prothrombin fits," Dr. Grody says. "I think it ought to be done."

"We didn’t go into methodology very much," Dr. Grody says, "but we did consider whether to do functional assays for FVL rather than direct DNA tests." DNA-based tests have advantages: They are not affected by concomitant therapy and better distinguish heterozygotes from homozygotes.

Finally, the committee said neither informed consent nor formal genetic counseling was needed with FVL testing. However, the physician should tell the patient that the test result could have implications for family members.