Coming up safe, not short, on
  platelets

Related article:
Highlights of impact survey

September 2005
Feature Story

Anne Paxton

The American Association of Blood Banks was ready to start requiring its members to test platelets for bacterial contamination more than 18 months ago. But there was a hitch in the process. Or there could have been.

The AABB wasn’t breaking entirely new ground, because the CAP already had a checklist question (TRM.44955) requiring a plan for bacterial detection for laboratory accreditation in transfusion medicine. But the Food and Drug Administration had consistently declined to impose a requirement itself.

Then, at the last minute, officials at the Department of Health and Human Services delivered a message to the AABB: Please hold off.

One week before the standard was due to take effect, HHS acting assistant secretary of health Cristina V. Beato, MD, wrote to AABB president Kathleen Sazama, MD, urging a delay in implementation. She cited "potentially serious and possibly unintended effects on availability of platelet products" and suggested waiting until a "clear plan" could be developed.

But Dr. Sazama responded that the AABB believed further delay would compromise public safety and public health, and the AABB went ahead with its plan. Though AABB Standard 5.1.5.1 adopted March 1, 2004, is voluntary, to be accredited as a blood bank, you must meet AABB’s standard of platelet bacteria detection.

And now there is both anecdotal and statistical evidence that, though blood centers have had to adapt, and it hasn’t been easy for a few facilities, the standard is making a difference in platelet safety—without the severe shortages that some had feared.

Several hundred infections, and somewhere between 67 and 333 deaths annually, are estimated to be caused by bacterial contamination of platelets in the U.S., making it by far the greatest infectious risk of blood product transfusion. Yet the federal government has no requirement that platelets, transfused about 4 million times a year, be screened for bacteria.

Unlike red cell or whole blood components, which are stored at 1° to 6°C, platelets must be maintained at 20° to 24°C to preserve their function and survival. That storage temperature allows a broad range of bacteria to multiply and potentially contaminate the unit.

For many years, blood experts have been concerned about the lack of regulation of platelets. "Currently the FDA doesn’t speak to bacterial contamination of platelets. You can be inspected by the FDA and do absolutely no testing for bacteria, and the FDA inspector will not cite you," says James P. AuBuchon, MD, chair of the CAP’s Transfusion Medicine Resource Committee and medical director of the blood bank and transfusion service at Dartmouth Hitchcock Medical Center, Lebanon, NH.

The FDA does regulate the instruments that can be used for bacterial testing. The agency has cleared the BacT/Alert test manufactured by BioMérieux, Durham, NC, an automated liquid culture system that measures increased CO2 produced by bacterial proliferation, and the Pall eBDS Bacterial Detection System made by Pall Medical, East Hills, NY, which measures changes in oxygen concentration as an indicator of bacterial growth.

A third FDA-cleared method is the ScanSystem manufactured by Hemosystem, a direct bacterial detection method based on fluorescent labeling followed by laser scanning and computer analysis.

"But that is simply a clearance to put in a package insert that the test can be used for that purpose," says Roslyn Yomtovian, MD, director of the blood bank-transfusion medicine service at the University Hospitals of Cleveland in Ohio. "So the only regulatory agencies that have actually given direction about a requirement are AABB and the CAP. The FDA hasn’t done this yet—but that’s not unusual."

As Dr. Beato’s letter confirmed, when the AABB imposed the standard, "there was concern that there would be increased frequency of platelet shortages," Dr. AuBuchon says. "Thankfully, that’s not occurred."

Surveys of blood centers since the AABB standard was adopted suggest that for most of them, new shortages of platelets have not been an issue.

Last fall, the AABB sponsored an impact survey of its member institutions, which was summarized before the HHS Advisory Committee on Blood Safety and Availability in January. (Related article: Highlights of impact survey.)

Three hundred fifty facilities, collectively responsible for collecting 43.3 percent of the nation’s random platelets and 65.9 percent of the nation’s apheresis platelets, responded to the survey from the blood centers’ Interorganizational Task Force on Bacterial Contamination of Platelets.

The majority (64 percent of hospitals, 68 percent of transfusion services, and 91 percent of blood centers) reported that the standard had no impact on their ability to provide platelets for transfusion, and about half said there had been no changes in their platelet inventory. Two-thirds indicated no increased platelet outdating, though a few cited substantial outdating, and one reported a 39 percent outdate rate.

The survey, which has been submitted for publication, showed a moderate shift to using apheresis platelets, though the task force cautioned that it could not link this shift to the imposition of the AABB’s standard, since "this appears to be a continuance of a pre-existing trend."

Also apparent was the nation’s transition to including bacterial detection as a form of quality control for platelet components. For apheresis platelets, well over 90 percent were tested by means of a culture technique while only a small portion of whole blood platelet concentrates were tested by culture.

A few blood centers reported an abrupt shift away from whole blood platelets, according to an earlier survey taken by America’s Blood Centers right after the AABB standard took effect. Four ABC centers said they had stopped making whole blood platelets because it was not feasible to them to implement bacterial detection for them, while others reported decreases in whole blood platelet production.

ABC chief policy officer G. Michael Fitzpatrick, PhD, told HHS that increased time, staffing, and expense were among the effects blood centers cited in that survey. "We added four staff to accommodate bacterial QC in the production area," said one, while a few noted a substantial increase in deliveries and purchases of additional incubators.

Changes in the timing of production were also noted: "We now release apheresis platelets in two batches rather than one; one early afternoon (used to be all) and one 7 to 9PM." And: "All WB platelets are manufactured as early in the day as possible so that sampling can start by 1PM the next day."

"Now that we’re screening platelets, the incidence of bacterial infection is reduced," says Mark Brecher, MD, professor of pathology and laboratory medicine at the University of North Carolina, Chapel Hill, and director of transplantation and transfusion services in the Mc Lendon Clinical Laboratories, "although the level of reduction has still to be quantified."

However, preliminary data from the American Red Cross, presented at the American Society for Microbiology meeting in June, show that since bacterial testing began, "they’ve had three cases of post-transfusion platelet sepsis, all with slow-growing organisms that were coagulase-negative staph," Dr. Brecher says.

"In the equivalent period of time before they began testing, they had 12 reports. That suggests that potentially three-quarters of the cases were prevented by the testing."

Dr. Yomtovian says she heartily endorses the standard and believes it has significantly lowered the risk faced by people receiving platelets.

"Even looking retrospectively, I have no qualms about having put the standard in effect, despite some of the other issues that have come out as a result. If you’re the patient and you need platelets, the single-donor platelets risk is much less than it was before," says Dr. Yomtovian, who is professor of pathology at Case Western Reserve University School of Medicine.

She suggests that the risk of contamination in whole-blood-derived platelet concentrates, also called random-donor platelets, is probably only marginally lower than before the standard. "Random platelets also have to undergo detection testing, but the methods used are much less sensitive in detecting bacteria than the methods that are employed for apheresis."

This "duality of quality" continues to be the most burning issue, in Dr. Yomtovian’s view. "One type of platelet is much safer than the other, and there has to be something done to bring the safety of platelets into equality."

For all types of detection testing, the blood components generally require time for the organisms to proliferate before they can be detected. Cultures conducted on the day of collection typically miss many bacterially contaminated units that would become dangerous once the bacteria grew during storage. As a result, platelets are held for 24 to 48 hours before tests are conducted.

"The downside of that is that every minute you add to the time you hold the units at the front end, you’re losing time to give them on the back end," Dr. Yomtovian says. "When you do bacterial testing, you’re chopping days off use of the unit."

"Often before you even get a platelet unit in inventory in the blood bank, it might already be in the third day of age. Previously it might have been in the second or first day, but you’ll never have that anymore. So you have much less time to move your inventory; therefore wastage has gone up."

At the same time, demand continues to rise. "It’s gone up every year more or less for the last decade," Dr. Yomtovian says. "I think it reflects an evolution in health care to more treatment for oncology conditions, trauma, and transplants, and all of those require platelets, of course."

"The standard hasn’t disrupted the system, but it’s certainly made providing platelets more complicated," says Dr. AuBuchon. The difficulty comes with platelet units derived from whole blood, which make up about 20 percent of all therapeutic doses of platelets transfused in the country.

"A few blood centers have taken up the charge and are culturing these units. But it’s more expensive, because one has to culture each unit individually. Rather than doing one culture per transfusion event as is done for apheresis units, one has to perform five or six for all the units that will be pooled together."

Since the units are only about 50 mL each, culturing each one individually also significantly diminishes the total volume available for transfusion. "Four or five mL out of a 300-mL unit is inconsequential, but four to 10 out of a 50-mL unit from a whole blood unit is 10 percent of the efficacy gone," Dr. Aubuchon says.

If the advice of manufacturers is followed and samples are obtained for both anaerobic and aerobic cultures, Dr. Yomtovian points out, "you could easily be using up to 15 mL of platelets—as much as a third of the unit."

As a result, most whole-blood-derived platelets are not being cultured. "The way most hospitals approach screening is by checking either the pH in the unit or the glucose in the unit," Dr. AuBuchon says. "One could check either one by automated methods like a pH meter or glucose analytic device, but many chemistry services are using urine dipsticks to measure these quantities."

"And if one combines the low inherent sensitivity with an analytic method like dipsticks, which is only semiquantitative, there is certainly the possibility of missing a truly contaminated unit," he adds. The unit would have to have more than a million organisms per mL to turn the tests positive.

Given these difficult testing logistics, and the multiplied risk of combining several units, why use whole blood platelets at all?

Some patients do require apheresis, Dr. AuBuchon explains, but for patients who are not immunocompromised, "whole blood is less expensive by virtue of traditional pricing for hospitals, and it has a long track record of being clinically efficacious, so many hospitals want to continue using it."

"We wouldn’t have enough platelets if we relied only on apheresis, " Dr. Yomtovian says. "We have tried to increase our apheresis platelets over time by producing them at our own donor center and purchasing from outside sources, but there would still be a gap between supply and demand."

"Some institutions continue to use pooled blood almost exclusively," Dr. Brecher says, "despite the fact that data suggest those units are not as safe compared with single donor. The rationale is largely economic, but, in addition, many experts feel it is wasteful to discard platelets given in whole blood units."

Rhode Island, for example, has not followed the countrywide shift to apheresis platelets. According to a report at the January meeting of the HHS Advisory Committee on Blood Safety and Availability, 80 percent of platelet transfusions in the state are whole-blood-derived.

But all platelets in Rhode Island are leukoreduced and cultured pre-storage, so the bacterial contamination risks are equivalent to those of apheresis, Joseph Sweeney, MD, director of coagulation and transfusion service at The Miriam Hospital, Providence, told the advisory committee.

Pre-storage culturing is not the most common practice elsewhere in the country. "No one in the field or the FDA is happy that we have two tiers of safety with respect to platelet transfusions, with apheresis units being tested effectively and whole blood for the most part not," Dr. AuBuchon says.

Pre-pooling of the random donor units, then culturing them, would solve the problem of lost volume. "If the FDA would allow these random platelets that come off of each whole blood donation to be mixed together at the point of collection and stored like that, you would create a single unit just like in apheresis, then testing could be done on the pooled unit," Dr. Yomtovian says. "But that has not been cleared by the FDA, so it can’t be done."

"Ironically, or paradoxically, one reason is if one unit is bacterially contaminated and you mix it with four or five that are not contaminated, you could actually get much more growth of the bacteria and it could be more dangerous."

"But it’s a circular argument," she adds, "because if you have a method to detect bacteria, then you would eliminate those units anyway. Many of us in the field have raised a question because pre-pooling would certainly enable testing of random donor platelets virtually on a par with single donor."

The FDA currently requires that transfusion occur within four hours of pooling. "The rationale is that providing a larger volume into which bacteria could grow would lead to a higher inoculant, leading to a more severe event for the recipient," Dr. AuBuchon says.

"But that theory doesn’t have much scientific support. Bacteria will top out at a particular concentration, probably on the order of 109 or 1012 /mL. The work we’ve done has indicated that’s not likely to happen, that the maximum concentration is usually not reached in platelet storage."

In fact, Dr. Brecher says, many donors have antibodies against bacteria, so pooling can bring self-sterilization of the unit, because "some bacteria that were going to grow, now won’t."

New testing technology is showing promise of bringing greater speed and efficiency to screening. For example, Verax Biomedical is developing a lateral flow device, similar to a pregnancy test, to test for bacterial contamination closer to the point of care.

"You would place a couple of drops of the platelet solution in the center of a plastic cartridge, close it, and after 20 minutes read a result, negative or positive, in a little window. It has a sensitivity of 1,000 organisms/mL," Dr. Brecher says.

Other companies are developing rapid, sensitive techniques to deal effectively with whole-blood-derived units. "But we’re not there yet," Dr. AuBuchon cautions.

In reality, it’s difficult to judge the sensitivity of culturing methods used now. "Obviously culturing is picking up something, because one out of about every 5,000 has been confirmed to contain bacteria. But we don’t know precisely what the sensitivity of this technique is because we don’t know how many are being missed," Dr. AuBuchon says.

There has never been a controlled study of that issue. He says: "The AABB bacterial contamination task force designed a protocol to prospectively determine the sensitivity of culturing, but the cost was prohibitive. It was estimated to cost from $8 to $10 million, so nobody stepped forward to fund it."

But evidence is forthcoming. Users of the apheresis platelets made with a cell separator manufactured by Gambro BCT Inc., Denver, in combination with bacterial testing with aerobic and anaerobic culture using a BacT/Alert, will be cleared for a storage extension to seven days, under an approach the FDA approved in March. "Gambro has received approval for seven-day storage of platelets collected in their apheresis system and cultured according to a standard protocol," Dr. AuBuchon notes.

"Any units ultimately not transfused will get cultured after their outdate, and that culture will essentially serve as the gold standard to determine whether or not the unit was truly contaminated. Any blood center wishing to use this approach must also agree to culture their outdated units."

Pall Medical has a similar application pending before the FDA for seven-day storage of platelets using its eBDS system. The possible sticking point for Pall is that the FDA wants detection of aerobic and anaerobic bacteria, but Pall’s system does not detect strict anaerobes.

"If you look at the cases of bacterial sepsis over the last several years due to platelet contamination, they have been predominantly aerobic," says Byron Selman, Pall Medical vice president of marketing. "We have submitted to the FDA an alternate approach that would lead to enhanced safety in blood, and we’ve been in discussions with the agency."

"This is a novel approach for the FDA," Dr. AuBuchon says. "It’s not an agency known for taking chances, or for allowing a change in established practice without data to document the sensitivity of a technique being used. I congratulate them, and I agree that a seven-day platelet that is cultured is superior to five years ago when we had a five-day platelet not cultured."

In Europe, where platelets are manufactured a little differently, whole-blood-derived platelets have been pooled for decades, and generally all cultured platelets have a seven-day shelf-life. "Their rate of contamination is no more or less than ours," Dr. Au Buchon says. While culturing is not universal in Europe yet, it is commonly performed in blood centers there and, in fact, "they prompted us to start culturing in 1999."

Richard C. Friedberg, MD, PhD, chairman of the Department of Pathology at Baystate Medical Center, Springfield, Mass., expresses reservations about the broad availability of long-shelf-life platelets. "Theoretically seven-day platelets are wonderful. The big problem with five-day platelets is always the three-day weekend, when Monday is a holiday so by Tuesday you’re still trying to live off Friday’s platelets, and Wednesday the same, because Tuesday’s platelets haven’t come out yet."

"But you’ve got to have automated systems at the speed you’d like, and in a large-scale system you have to get the volume to the point where it makes sense to do them.

"When we have a platelet collection system tightly associated with an approved rapid method to confirm that the units are free of bacterial contamination, then you can start talking about seven-day platelets that are realistic."

While these issues are being worked out, laboratory accreditation programs continue to strengthen their oversight of bacterial testing for platelets. On the drawing board for the CAP’s Transfusion Medicine Resource Committee is a proficiency-testing program. "We hope through PT that laboratories will also begin to determine the sensitivity of these surrogate techniques like glucose or pH," Dr. AuBuchon says.

"This PT system needs to be applicable to people who are culturing platelets as well as those laboratories detecting bacteria through pH or glucose testing," he says. "So it’s a bit of a challenge to come up with a system applicable to two very different approaches."

But a pilot is underway, and they hope to be able to offer something next year.