February 21, 2003

VUMC scientists first to link gene to blood loss after surgery

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The research, led by Dr. Brian S. Donahue at VUMC, is part of a new era in medicine — customized therapies for individual patients. (photo by Dana Johnson)

VUMC scientists first to link gene to blood loss after surgery

Bleeding after cardiac surgery is a major clinical problem, consuming up to 20 percent of the nation’s blood supply. Despite some understanding of the risk factors that contribute to increased blood loss, there is still considerable patient-to-patient variability, said Dr. Brian S. Donahue, assistant professor of Anesthesiology.

Donahue and colleagues are the first to show that a common genetic variation contributes to a patient’s tendency to suffer bleeding complications. The Vanderbilt Medical Center investigators report Feb. 25 in Circulation that cardiac surgery patients who have a different genetic form of one clotting factor lose less blood and are less likely to receive blood transfusions.

The findings are part of a revolutionary new era in medicine, one in which therapies will be customized for individual patients, based in part on the genes they carry. That is the hope anyway, Donahue said.

“If we can outline a patient’s specific risk factors for given complications, then we can better tailor our therapeutic approach,” he said.

The current study focuses on factor V (“factor five”), one of the proteins essential to normal blood clotting. A variant form of the gene, called factor V Leiden, is present in about 5 percent of the white population in the United States, making it one of the most common inherited blood coagulation mutations. Individuals with factor V Leiden are at increased risk of forming blood clots, especially deep venous thromboses.

Because factor V Leiden carriers have blood with an increased tendency to clot, Donahue and colleagues wondered whether the mutation might actually protect against blood loss and transfusion in patients undergoing cardiac surgery.

They enrolled 517 cardiac surgery patients in the study, 26 of whom turned out to have one copy of the factor V Leiden gene (and one normal factor V gene).

By measuring multiple variables and performing statistical comparisons, the investigators were able to demonstrate that patients with a factor V Leiden gene lost about a third less blood compared to patients with two normal factor V genes. In addition, about half of the factor V Leiden patients received blood transfusion after surgery, compared with nearly three-fourths of the patients without factor V Leiden.

The study is the first to link a common genetic variant to a clinically relevant outcome of cardiac surgery, Donahue said. “You’re almost twice as likely to leave the hospital free of a blood transfusion if you have factor V Leiden vs. if you don’t,” he said.

The current findings demonstrate that factor V Leiden offers a protective effect with respect to blood loss and transfusion after cardiac surgery. But the gene variant may also play a sinister role.

“The question now is does factor V Leiden place cardiac surgery patients at increased risk for thrombosis, a potentially catastrophic complication,” Donahue said. Ongoing research will assess the impact of factor V Leiden on thrombosis following surgery. If factor V Leiden increases risk for thrombosis, genetic screening for the mutation could become routine.

While the current findings won’t immediately change clinical practice, Donahue said, they provide evidence that genetic variation impacts important surgical outcomes, supporting the need for additional studies in this area.

Dr. Jeffrey R. Balser, James Tayloe Gwathmey Professor and Chair of Anesthesiology, hopes to increase this type of research at Vanderbilt by developing the first major center for genomics in perioperative medicine. “This paper helps put us on the map,” Balser said.

Physician-scientists like Donahue who straddle laboratory bench and patient bedside are key to these efforts and are aided in developing their research projects by the Vanderbilt Physician Scientist Development Program (VPSD), which Balser founded and directs.

The VPSD provides two years of salary support to new physician-scientists so that they can spend 75 percent of their time engaged in research.

“The VPSD was a program essential for getting my project off the ground,” said Donahue, who was mentored by senior scientist Dr. Alfred L. George Jr., Grant W. Liddle Professor of Medicine. “It bridged the gap for me, allowing me the time to gather data so I could submit my own NIH application.”

“The VPSD has been phenomenally successful,” Donahue added. “There are probably at least a dozen federal grants now at Vanderbilt that were made possible by the VPSD.”

Donahue’s co-authors on the Circulation paper are Drs. George, David Gailani, Michael S. Higgins, and Davis C. Drinkwater. The research was supported by the National Institutes of Health and by a Clinical Research Starter Grant from the Foundation for Anesthesia Education and Research and Astra-Zeneca Pharmaceuticals.