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Duke Researchers Identify Seven Genes That May Double Prediction of Heart Surgery Bleeding

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Medical researchers at Duke University Medical Center have identified a group of seven genes that, when evaluated along with traditional risk factors, may lead to a diagnostic risk stratification tool that is twice as effective as clinical indicators at predicting bleeding after heart surgery.

The research, which will be published in the June issue of the Journal of Thrombosis and Haemotology, examined blood samples from 780 patients taken before coronary artery bypass grafting, the most common heart surgery, and compared the amount of bleeding each patient experienced after the procedure. The research was supported by the US National Institutes of Health, the American Heart Association, and Bayer Pharmaceuticals.

Drugs like Bayer's [Trasylol] are used to reduce the risk of bleeding after heart surgery, Ian Welsby, lead author of the paper and Duke anesthesiologist, told Pharmacogenomics Reporter. The indications for that drug, and others like it, stipulate that patients should receive it if they are undergoing a follow-up surgery, or if they are at risk of bleeding according to traditional clinical indicators, he said. "Genetic screening could help identify high-risk patients who may benefit by these supposedly expensive therapies up front, which would protect them from bleeding downstream," he said.

During surgery in which a heart-lung machine is used, patients are given a high dose of heparin blood thinner to inhibit clotting that can be induced by the surface of the pump. But a small amount of coagulation still occurs. "And then, in the snap of a finger, you want to reverse the process at the end of the surgery to stop them from bleeding to death," said Welsby. The day after surgery, aspirin is administered to inhibit clotting as a result of tissue grafts. Expensive anti-clotting agents can be administered in high-risk situations.

None of the patients in the study received Trasylol, and the research was not conducted in support of Bayer products, said Welsby.

The Duke investigators examined the effect of 19 polymorphisms in 13 genes shown by other studies to be involved in clotting. "[W]e didn't just look at single-gene studies. We wanted to get a feeling for gene-gene interactions, because the etiology of bleeding after heart surgery is multifactorial," Welsby said. The team found a total of seven polymorphisms, including alleles of angiotensin converting enzyme, tissue factor genes, platelet surface receptors, coagulation proteins, and a glycogen receptor.

The researchers identified genes that were "at least as predictive" as the clinical factors normally used to determine the risk of bleeding, such as platelet count, age, and size, said Welsby. "There's still a lot of variability that remains unexplained," but combining the genetic and clinical factors doubled the predictability of bleeding, he said.

While a genetic-based test for bleeding risk "could be applicable in other areas," Welsby said that it would most likely find use in coronary artery bypass surgery, which about 400,000 patients undergo every year in the United States. Of these patients, approximately 25 percent to 50 percent need blood transfusions, 5 percent need a "large blood transfusion," and 2 to 3 percent undergo further surgery due to bleeding, Welsby said.

"The more you bleed, the worse your outcome is," Welsby said. It is difficult to pick out the cause of poor outcomes, but "most likely, the more you bleed, the more you're transfused, and there are reams of data that show transfusion is bad for you," he said.

The next step is to validate the genetic factors identified in the current study, and to add intermediate markers, such as platelet function and platelet count, and mechanistic markers as well to "make a scientific story with a mechanism that seems plausible," Welsby said.

Duke holds the patents derived from the research. No companies have yet shown interest in developing a diagnostic based on the group's work, to the best of Welsby's knowledge.

"We've got a fairly large peri-operative genomics research project underway looking at various outcomes in a large number of patients, which is spearheaded by the anesthesiology department, and I'm examining the outcome of bleeding," said Welsby. The group is studying a static set of genomic markers, "and from that standpoint, these studies are always a little bit behind the times," he said.

— CW

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