Blood Clotting Disorder -- A New Heritable Risk Factor?

March 19, 1998

SANTA FE, N.M., March 19 -- Blood clotting abnormalities, which have emerged as a potential risk factor for heart disease and stroke, appear to run in families, according to two studies reported today at the American Heart Association's epidemiology and prevention conference.

Researchers at the Framingham Heart Study have identified two types of blood clotting abnormalities that increase the tendency of the body to form dangerous blood clots on the inside lining of the blood vessels. The clots can obstruct blood vessels, causing a heart attack or stroke. In both types the abnormalities appear to have a strong genetic component.

James E. Muller, M.D., chief of cardiology and a professor at the University of Kentucky Medical Center, and co-author of one study, says the genetic research on clotting abnormalities has important implications.

"The traditional risk factors account for only one-half of heart attacks, so we need to look beyond cholesterol and other widely recognized risks," says Muller. "This research is an important step in understanding risk factors for clotting that will improve our ability to prevent heart attacks."

Geoffrey H. Tofler, M.D., co-investigator on both studies, says the research sheds light on characteristics -- besides the more traditional risk factors such as high blood pressure and elevated blood cholesterol level -- that may make a person more prone to heart disease or stroke.

"Most physicians should be aware that there are other contributors to heart disease risk," says Tofler, associate professor of cardiology at Beth Israel Deaconess Medical Center in Boston. "Where there is premature heart disease and a strong family history, there might be a genetic basis for clotting abnormalities. We are interested in the role of genetic factors in heart disease, and what factors might alter the chemistry of blood clotting." In one study, Tofler and researchers at Beth Israel Deaconess Medical Center found a genetic basis for elevated levels of Factor VII, a blood clotting factor associated with increased cardiovascular risk. Factor VII is a clotting agent normally broken down by the liver.

They studied a genetic variation (polymorphism) on the Factor VII gene coding for two amino acids -- arginine (Arg) and glutamine (Gln). Polymorphism is the ability of certain alleles (genes) to appear in different combinations at the same location, or locus, on the human chromosome.

In 1,816 individuals in the Framingham Offspring Study, researchers found that the polymorphism of the Factor VII gene determined Factor VII levels in the bloodstream. Levels were higher in people who had two copies of Arg (homozygous) than in those who had one copy of Arg (heterozygous) of the gene.

Gene type accounted for 7.3 percent of variance in Factor VII levels, while environmental factors such as blood levels of a type of fat called triglyceride or smoking accounted for another 12.3 percent. However, unlike prior studies, this study did not detect an interaction between the polymorphism and traditional risk factors such as cholesterol levels or fasting triglycerides.

DaLi Feng, M.D., a research fellow in cardiology at Deaconess who presented the results, says the study provides evidence of a genetic component in blood clotting. "One could speculate that one gene form may lead to increased risk of blood clotting events and the other is a protector," he says. "However, this needs to be studied further."

The second study, reported by Christopher J. O'Donnell, M.D., medical officer and cardiologist at the National, Heart, Lung, and Blood Institute and the Framingham Heart Study, compared blood platelet aggregation in 848 pairs of siblings and 387 unrelated spouses. "A substantial portion of the variation in platelet aggregation appears to be genetic, an important finding in the general population," he says.

Platelets are small disk-shaped blood cells that clump together to form blood clots. Receptors, located on the platelet surface, act like docking sites and determine the "stickiness," or aggregation ability of platelets. Some individuals may have "hyperactive receptors," which can accelerate platelet aggregation, causing them to stick to each other more readily, often forming clots. Platelet hyperreactivity has been associated with increased cardiovascular risk, but until now scientists have believed environmental factors were primarily responsible.

The reactivity of platelets of Framingham siblings was tested with agents that lead to platelet aggregation.

"The correlation of responses among family members was striking, even after we adjusted for other factors which have major effects on platelet function, such as cigarette smoking, triglyceride levels, diabetes and cholesterol," says O'Donnell. "It is conceivable that a substantial portion of platelet aggregation in individuals is really due to genetic differences in receptors."

Now that researchers know that there is a genetic component, new treatments targeted to the abnormalities and individuals at risk may be developed. "The next step is to identify specific genes to explain this genetic influence," says O'Donnell. "Once they are identified, we can potentially develop better therapies against the more vigorously reactive platelets and identify patients at greatest heart attack risk for whom preventive therapies can be targeted."

Further research will be needed to determine if the clotting factors can be used to screen individuals at increased risk for heart disease and stroke.

Feng's co-authors are Klaus Lindpaintner, M.D.; Martin Larson, S.D.; Izabella Lipinska, Ph.D.; Christian Schimitz, M.D.; Patrice Sutherland; Michael Johnstone, M.D.; and Daniel Levy, M.D.

The study was presented at the American Heart Association's 38th Annual Conference on Cardiovascular Disease Epidemiology and Prevention.

O'Donnell's co-authors are Martin Larson M.D.; Richard Myers, Ph.D.; Daniel Levy, M.D.; and Geoffrey Tofler, M.D.
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Media advisory: Dr. Feng can be reached at (617) 632-7684; Dr. O'Donnell can be reached at (508) 935-3435. (Please do not publish telephone numbers.)

NR 98-4870 (Epi98/Odon)
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American Heart Association

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