6 Local Deaths Lead to Plasma Warning

The deaths of six liver transplant patients at Cedars-Sinai Medical Center, all associated with transfusions of a highly touted new form of blood plasma, have led to a warning against use of the product in such surgeries or when patients have severe liver disease.

Six of 31 or 32 liver transplant patients at Cedars-Sinai died after receiving the new form of plasma between April and December 1999. But the company that manufactures the product did not issue the “black box” warning--the most severe kind--to doctors and health-care providers until two months ago, more than three years after the Los Angeles deaths.

The Massachusetts-based manufacturer, V.I. Technologies Inc., or Vitex, had first advised doctors in October 2000 of a possible connection between the cluster of deaths and the form of plasma called Plas+SD or SD Plasma, which was distributed by the American Red Cross.

The “important prescribing information alert” was distributed through the U.S. Food and Drug Administration’s national safety-reporting clearinghouse, MedWatch, almost a year after federal officials began investigating the Cedars-Sinai deaths.

Cedars-Sinai officials in 1999 had alerted both the FDA and the U.S. Centers for Disease Control and Prevention to the deaths, which involved unusual clotting or excessive bleeding. They also suspended use of the plasma.

But the hospital did not tell the families of patients about the possible problems with the plasma until this week, when the Cedars-Sinai deaths were reported in Newsday, a Cedars-Sinai spokeswoman acknowledged.

Newsday based its findings primarily on FDA records. The newspaper reported that the patients ranged from a 64-year-old woman to a pregnant 17-year-old.

The Cedars-Sinai spokeswoman, Grace Cheng, noted that a CDC report in April 2001 on the deaths found “no direct cause and effect” relationship between the plasma and the deaths, but concluded that there may have been a correlation.

“We always want to have as much information, and as much definitive information, as we can,” Cheng said.

When the CDC found that it could not demonstrate a direct link between the plasma and the deaths, “that brings up the question, then: Given that these cases were so complex and so high-risk, was there something to say at that point?”

The hospital decided to tell the families after the Newsday articles were published because “we don’t want there to be any misunderstanding,” she said.

The company’s March warning came after four more deaths associated with the plasma were reported to MedWatch. Those deaths occurred between August 2000 and March 2001, according to FDA officials.

The four additional deaths, unlike those in Los Angeles, were not clustered in a single location, said federal officials, who would not specify where they occurred. Those deaths included both transplant recipients and patients with severe liver disease who did not undergo transplants.

In addition to its recommendations against using the plasma in the cases of patients with liver disease, the March warning advised that any patient being given large amounts of SD Plasma should be monitored closely for excessive bleeding and complications

The six deaths among Cedars-Sinai liver transplant patients amount to a mortality rate of about 20% (Cedars-Sinai says there were 31 patients altogether; the FDA says there were 32). That rate is somewhat higher than usual for liver transplants.

However, Cheng said the six who died were “very, very seriously ill patients with a lot of complications.” Given that, she said, what was unusual was not the number who died, but the way they died, with far more clotting problems than usual.

No unusual deaths were noted among more than 100 other, non-liver patients who received the plasma at Cedars-Sinai, Cheng said.

Shortly after the sixth death, hospital officials decided that “it would be prudent to discontinue the use of SD Plasma for all patients at the Medical Center,” according to a report the hospital submitted to the FDA, which was obtained by Newsday

“They started using [SD Plasma] at a particular time, they noticed deaths were occurring, they stopped using it and the deaths stopped,” said Dr. Mark Weinstein, FDA’s director of the Division of Hematology, Center for Biologics Evaluation and Research.

SD Plasma, developed as a way to enhance the safety of blood plasma transfusions, combines donated plasma from as many as 2,500 people and then scrubs it of many--but not all--viruses by using a detergent. SD stands for solvent detergent.

The product was touted by the American Red Cross in a 1999 news release as the newest way to “help safeguard the blood supply.” The reason for that, the organization said, is that it destroys a wide range of viruses with fatty coatings, including HIV and hepatitis B and C.

The organization at that time said that it was accelerating plans to distribute the product to 2,000 hospitals and would offer “favorable pricing initiatives” to make it available to more patients.

At $125 a unit, it is more than twice as costly as the alternative, fresh frozen plasma, said Dr. Gary Zeger, medical director of the USC Blood Center. He said the American Red Cross invested heavily in the product and “very, very aggressively” promoted its use.

“A lot of research and development and resources went into this product, and I think they depended on [its] success,” he said.

A spokeswoman for the American Red Cross said late Thursday that no one was available to comment about the nonprofit organization’s distribution of the product.

A spokesman for V.I. Technologies declined comment, saying that the company had divested the unit that made the plasma and no longer manufactured it.

Jim Moose, president and CEO of the company that bought the unit, Precision Pharma of Melville, N.Y., said his company had never made the plasma. He said manufacturing was discontinued before V.I. Technologies divested the unit last August.

At the time of the deaths at Cedars-Sinai, federal officials said, only one other hospital was known to have used SD Plasma in liver transplant surgeries. FDA officials would not name that hospital.

Many hospitals have used the plasma and continue to do so, for other surgeries.

Federal officials Thursday defended the length of time it took from the first reports of deaths and the decision to warn doctors and health-care providers about a possible link between severe reactions and use of SD Plasma.

Weinstein, one of the leaders of the FDA’s investigation, said Thursday that the Cedars-Sinai deaths immediately raised investigators’ concerns because of their “very unusual” nature.

But, he said, attempts to find a direct link between the product’s use and the deaths proved difficult.

“We conducted an epidemiological survey, and asked: Is this occurring in only one hospital? Is it lot-specific? Is it a result of using many lots? Was there something unusual about how it was manufactured or how it was being used?” Weinstein said. “And this is where it really gets very complicated: We don’t have a true absolute cause and effect relationship between use of this product and the particular event.”

FDA officials said that although they found no direct link between the deaths and SD Plasma, there were “working theories” about why small clots formed in the patients who died, cutting off their blood vessels.

Weinstein said SD Plasma contains lower levels of certain proteins that could have helped prevent clotting than fresh frozen plasma.

In addition, higher volumes of the product are needed in liver transplant cases than in most procedures.

Though the Red Cross touted the safety of the new plasma product and many European countries have used it for years, concerns about pooling plasma donations have arisen among some health-care professionals.

Although the detergent kills a broad array of viruses, there are some that survive.

Weinstein said that those risks are “a major concern” because the new product pools plasma from so many donors. He noted that the product remains licensed for use.

“This is a matter of physicians’ having to weigh the pluses and minuses,” he said.