PATHOLOGY

Edited by: Thomas W. Durso BLOOD BROTHER: Joseph Miletich of Washington University examined whether a mutation in a blood-coagulation gene can lead to the formation of blood clots in veins and arteries. P.M. Ridker, C.H. Hennekens, K. Lindpaintner, M.J. Stampfer, P.R. Eisenberg, J.P. Miletich, "Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men," New England Journal of Medicine, 332:912-7, 1995. (Cited in more than 120 papers as of April 1997) Comments by Joseph P. Miletich, division of laboratory medicine, Washington University School of Medicine, St. Louis. According to coauthor Joseph P. Miletich, a professor of internal medicine and pathology at Washington University School of Medicine and medical director of the Barnes-Jewish Clinical Laboratories in St. Louis, this paper was the first to report with a high degree of confidence the prevalence of a mutation in the gene that encodes blood coagulation factor V in a United States population. Examining a large group of American men, Miletich's team found the rate for the mutation to be about one in 19. "Based on smaller studies around the world, the prevalence of this mutation varies from zero to more than 10 percent, so an accurate number for the U.S. was needed to design further studies," Miletich states. The scientists also looked at whether the mutation was a risk factor for venous thrombosis (the presence of blood clots in veins) or arterial thrombosis (the presence of blood clots in arteries). Prior research had offered sketchy evidence for an increased risk factor for venous thrombosis, but conclusions on arterial thrombosis were even more unclear. The study reported in this paper showed the mutation does not pose a significant risk for arterial thrombosis; there is a risk for venous thrombosis, although a somewhat smaller one than previously believed. "Estimating the risk of an inherited trait for future events can be quite difficult because of the problem of ascertainment bias," Miletich acknowledges. "The easiest way to find people with the mutation is to study people who already have the disease that it might help cause. When you do that, it's difficult to ensure you don't overestimate the risk attributable to this mutation, since people with the disease may have a host of other unrecognized risk factors." Miletich offers a variety of reasons to explain why the paper is so well-cited: The paper established the prevalence in the U.S. population, which is a "big market"; it convincingly showed the mutation is not a significant risk factor for arterial thrombosis; and it determined the relative risk for venous thrombosis "with reasonable confidence limits." While only one in every 2,000 to 5,000 people shows clinical signs of an inherited predisposition for venous thrombosis, the coagulation factor V mutation occurs in one of every 19 people, leading Miletich to conclude that "this mutation can't confer a do-or-die risk." He pointed out this paradox in a previous report dealing with another risk factor for venous thrombosis, inherited protein C deficiency (J.P. Miletich et al., New England Journal of Medicine, 317:991-6, 1987). Since this condition "is much harder to document and is 10 to 20 times less common than the mutation in factor V, direct evidence for additional risk factors could not be found in the small numbers of people that could be studied," he comments. That changed with the factor V mutation. Researchers can now look for, and are finding, other risk factors. Miletich reports: "Now when families with a tendency for venous thrombosis are investigated, they often have this mutation in conjunction with other risk factors. That ties in with some of what we've done" since then. Miletich's more recent work showed that the prevalence of the mutation is different among ethnic populations within the U.S. (P.M. Ridker et al., JAMA-Journal of the American Medical Association, 277:1305-7, 1997) and that the mutation confers a much higher risk of suffering recurrent venous thromboses (P.M. Ridker et al., Circulation, 92:2800-2, 1995). In addition, he reported that the level of an amino acid called homocysteine is a moderate risk factor that magnifies the impact of the factor V mutation (P.M. Ridker et al., Circulation, 95:1777-82, 1997). "In our cohort, the independent risk from the mutation and from an elevated homocysteine level are both about fourfold. Together they multiply and seem to confer about a 20-fold risk," Miletich states. Finally, age is a risk factor, with the risk rising exponentially for venous thrombosis (P.M. Ridker et al., Annals of Internal Medicine, 126:528-31, 1997). "This risk with age is amplified with the mutation," he notes. Miletich concludes: "The mutation seems to make other risk factors even higher. Total risk seems to be more than just additive. The search for more risk factors will continue. I think the paper will continue to be cited often because newly identified risk factors will be investigated in conjunction with the factor V mutation."

PATHOLOGY

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