Specific variants of genes predict bleeding after heart surgery

May 4 2005

Duke University Medical Center researchers have found that the presence of specific variants of genes that control clotting and the contractility, or "tone," of blood vessels can double the ability of physicians to predict those heart surgery patients at greatest risk of bleeding after surgery.

The issue of post-operative bleeding is important, the researchers said, because patients who suffer such episodes have increased rates of additional medical problems and even death. Furthermore, decreasing the rate of postoperative bleeding can have important implications for the health care system, they continued, since an estimated 20 percent of the nation's blood supply is used to treat these patients.

"While larger studies are needed to investigate the genetic associations we have uncovered, if our observations are confirmed, genetic screening could become an important part of our pre-operative evaluation of heart surgery patients," said Duke anesthesiologist Ian Welsby, M.D., lead author of a study to be published in the June edition of the Journal of Thrombosis and Haemostasis but appearing early on-line.

Currently, physicians base their predictions of who is likely to bleed on such patient characteristics as weight, size and blood count. In their consideration of risk, they also take into account factors that may come into play during the actual surgery, such as the number of vessels being bypassed, the degree of atherosclerotic disease and use of the heart-lung machine to keep blood pumping while surgeons operate on the stopped heart.

"However, these risk factors we use now are poorly predictive of which patients are more likely to bleed," Welsby continued. "Also, these factors are only partially successful in accounting for the striking variability in outcomes among patients undergoing heart surgery."

Within the circulatory system, three main factors control bleeding or clotting – blood vessel constriction, platelet activation and the activity of clotting factors that circulate in the blood. Abnormalities in any of these areas can lead to potentially dangerous bleeding or clotting.

According to Welsby, past studies have demonstrated a genetic component to the activation of platelets and clotting factors. However, since there has only been one study that focused on a single variation -- or polymorphism, in connection with post-surgical bleeding, the Duke team believed that multiple genes and their interactions may be involved.

The researchers first selected 19 different polymorphisms of 13 candidate genes that past studies have shown have an effective on the blood's ability to clot. They then correlated genetic information from blood samples taken from 780 patients prior to heart surgery at Duke University Hospital with the amount of bleeding after surgery.

"Genetic analysis revealed that seven polymorphisms of platelet surface receptors, coagulation proteins and angiotensin converting enzyme (ACE) demonstrated a significant association with increased bleeding after heart surgery," Welsby said. "These genetic factors are independent of the clinical characteristics used to predict bleeding and appear to explain at least as much of the variation seen among patients.

"For this reason, we believe that adding the genetic information to our existing risk stratification factors should be able to double our ability to predict who is at greatest risk of bleeding, "Welsby continued. "While substantial variability in bleeding remains unexplained, these novel genetic approaches may have the potential to expand our understanding of bleeding after heart surgery."

Welsby said he found it interesting that one of the polymorphism (ACE D/I) was for a gene involved in vascular tone, the ability of vessels to contract or expand appropriately, which represents a new line of research that should be pursued along with the traditional blood clotting factors.

As is true of many genetic analyses, the current study cannot explain the mechanisms involved in the increased risks, said Welsby. He said that further studies will be needed to better understand not only the roles of the polymorphisms that have been identified, but the interactions between them and other potential genetic variants.

Welsby also said that a better knowledge of who may be at risk for bleeding would be useful because there are effective, though expensive, drugs that are currently reserved for those patients at highest risk, based on their clinical characteristics.

Earlier this year, members of the same research team found that patients with a different set of polymorphisms were at a two to four times as likely to suffer kidney damage as a result of major heart surgery.

The research was supported by the National Institutes of Health, the American Heart Association and Bayer Pharmaceuticals Corp.

Other members of the team, all from Duke, are: Mihai Podgoreanu, M.D., Barbara Phillips-Bute, Ph.D., Joseph Mathew, M.D., Peter Smith, M.D., Mark Newman, M.D., Debra Schwinn, M.D, and Mark Stafford-Smith, M.D. All are members of Duke's Perioperative Genetics and Safety Outcomes Study (PEGASUS) team.