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Clotting Aid May Cause Complications Later

Repeated use in surgeries leads to immune-system problems

WEDNESDAY, Oct. 31, 2001 (HealthDayNews) -- American researchers are raising a red flag over a substance used to control bleeding during hundreds of thousands of surgeries every year.

Bovine thrombin, which promotes clotting, may trigger an abnormal immune response that could cause serious complications, including bleeding to death, in people who subsequently are exposed to the substance, warn scientists at the Duke University Medical Center in Durham, N.C.

A representative of a major American manufacturer of bovine thrombin says he is not aware of any such complications.

Thrombin is an enzyme that plays a critical role in the end stages of blood clotting. Doctors routinely applied human thrombin to incision or suture sites during surgery to control bleeding until 1997, when the Food and Drug Administration (FDA) banned its use over concerns of spreading hepatitis B from blood used in certain thrombin preparations.

Bovine thrombin subsequently became the main source of thrombin in the United States, where it's currently used in an estimated 500,000 or more surgeries a year.

Dr. Jeffrey Lawson, a biochemist and assistant professor of surgery at Duke, says he began to study thrombin about a decade ago, when a colleague sent him a blood sample from a man whose blood would not clot properly.

In the sample, Lawson found an antibody for bovine thrombin, which seemed to be interfering with the man's own blood clotting systems. By studying the man's medical records, Lawson found the man had gone through several surgeries, during which his doctors probably had used bovine thrombin to stop localized bleeding.

The bovine version is similar to human thrombin, but Lawson says a carbohydrate in bovine thrombin called galactose-alpha 1-3-galatose (alpha-Gal, for short) may be triggering the human immune system, because humans don't produce alpha-Gal.

Exposure to thrombin sets off a series of reactions, Lawson says. The first time a person is exposed, he or she makes antibodies to the foreign substance.

But if the bovine thrombin is reintroduced, as it would be during a second surgery, for example, the antibodies produced after the first exposure can't distinguish between bovine and human thrombin, and the person's immune system begins to attack his or her own body. Details appear in the November issue of The American Journal of Pathology.

Previously, after a series of reports from different research teams chronicling such cases, Lawson's team reported in the Annals of Surgery that more than 90 percent of 150 heart surgery patients developed antibodies to bovine thrombin, and 30 percent developed antibodies that also reacted to human proteins.

People who had antibodies to bovine thrombin before their surgery also faced a higher risk of post-operative complications, such as spontaneous bleeding from their intravenous injection sites, Lawson says.

To examine the problem, Lawson and his team created a genetically engineered strain of mice that lack the gene for alpha-Gal, making them more like human models.

When mice without the gene were exposed to bovine thrombin, they showed an immune response similar to the human reaction to the clotting agent. Moreover, the mice developed an autoimmune syndrome similar to the human disease called lupus.

"These mice got profoundly sick," suggesting that exposure to bovine thrombin alone can cause autoimmune problems, says Lawson.

Lawson says many previous studies involved patients treated with Thrombogen, a bovine thrombin solution that is 15 percent to 20 percent pure, while others have used the newer Thrombin-JMI, which is 90 percent to 95 percent pure.

"The real question is, 'Does that make any difference?' " asks Lawson. He says that there have been no clinical trials suggesting the newer formulation is safer. "In our mice, it didn't make any difference," he says.

And a half-million Americans exposed to bovine thrombin annually raises serious concerns, Lawson says.

"The widespread use of this agent … should be really restricted. We should reserve these kinds of preparations for only life-threatening [situations]," he says.

"We're hoping to coax the FDA into looking very seriously at this topic," he says.

Dr. José Cintron, associate professor of surgery at the University of Illinois College of Medicine in Chicago, says, "Bovine thrombin, even the current, purer formulations, probably should be removed from the shelves based on the information that he [Lawson] presented."

But James Green, the senior director of corporate affairs at Jones Medical Industries Inc., says to his knowledge, bovine thrombin is safe. The Bristol, Tenn.-based company makes Thrombin-JMI from cow blood and lung tissue.

"I'm not aware of any problems with thrombin," he says.

Pure human thrombin still is banned by the FDA, but other clotting substances, while not as potent, are available. These include human fibrin sealant, which mixes human thrombin and human fibrinogen. Because it contains only human material, Lawson says it theoretically should be safer, although further studies are needed.

What To Do: Check how blood works from or test your blood I.Q. with the National Heart, Lung and Blood Institute.

SOURCES: Interviews with Jeffrey H. Lawson, M.D., Ph.D., assistant professor, division of general surgery and department of pathology, Duke University Medical Center, Durham, N.C.; José R. Cintron, M.D., associate professor, division of colon and rectal surgery, department of surgery, University of Illinois College of Medicine, Chicago, and James E. Green, senior director, Corporate Affairs, Jones Medical Industries Inc., Bristol, Tenn.; November 2001 The American Journal of Pathology
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