Vol. 11 •Issue 2 • Page 55
Transfusion Medicine: A State of Constant Change
Out with the old and in with the new? A look at the established techniques in transfusion medicine and the new methods that have a promising future.
Sept. 11, 2001 changed the way people thought about giving blood. Almost everyone that could showed their compassion in every state by giving blood, hoping that it would reach someone who desperately needed it. But not many of these Americans understand what happens after they leave the clinic and what their blood must go through before it can be put to good use. Over the years, the practice of transfusion medicine has gone through quite a few changes to ensure that each individual receives the best quality blood. Some of the innovations have taken a strong hold and prove to be contributing a great deal to keeping patients safe during transfusions; others are still under way, trying to prove that they can be just as helpful Éor even better.
According to the American Association of Blood Banks, a series of tests are performed on blood after it is taken from the donor. These include tests for the hepatitis viruses B and C, human immunodeficiency viruses (HIV) one and two, human T-lymphotropic viruses I and II and syphilis. Some of the specific tests performed are the hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus antibody, HIV-1 and HIV-2 antibody, HIV p24 antigen, serologic test for syphilis and nucleic acid amplification testing.1
Examining the Options Nucleic Acid Amplification Testing
One of the newest methods to be trialed as a way to enhance the safety of blood and, hence, the safety of transfusions is nucleic acid amplification testing (NAT). NAT detects the genetic material of a transfusion-transmitted virus pool of donor samples. When viral nucleic acid is detected, the individual samples in the pool are then tested individually to determine which sample contributed to the contamination. The hope is that NAT will allow detection of infections even in the window period–the time when an individual contracts a disease to the time when the body begins to make antibodies for that disease.
It began in 1999 and is being performed in blood centers under the Food and Drug Administration’s (FDA) Investigational New Drug applications; the operations of the tests are under the surveillance of the FDA. Since its beginning, NAT has proved that is a worthwhile operation. Linda A. Chambers, MD, FASCP, senior medical director of the American Red Cross, knows first hand how this application has contributed to the safety of transfusions.
“Two and a half years of testing and millions of dollars, the Red Cross has found three HIV positive and 53 hepatitis C (HCV) positive samples that would have been missed by routine testing,” Dr. Chambers says.
In fact, the 53 samples that tested positive for HCV were not seropositive samples at the time, so Dr. Chambers admits that these would have surely been missed. Dr. Chambers also reports that there has not been any reported cases of HIV or HCV disease transmission since NAT testing began.
One interesting element to this data and also another indicator that this technology is an important advance in transfusion medicine is that all but one of the 53 HCV positive individuals eventually seroconverted. In fact, according to Dr. Chambers, this one individual is not making antibodies for HCV even though the virus has been detectable in his system for over two years.
“NAT testing has disclosed that there is a low rate of people who carry HCV without ever becoming seropositive, which points out the limitation of antibody screening as an infectious disease screening technique of the blood supply,” Dr. Chambers explains.
Paul Ness, MD, professor of Pathology, Medicine and Oncology and director of Transfusion Medicine at Johns Hopkins University agrees that NAT has been very beneficial. He believes that it is more effective than antibody testing alone.
“When you add in NAT testing you cut the window for HIV by a couple of days, but for HCV it is cut in half. So if the window was 70-80 days, it gets cut down to 30 days,” Dr. Ness says. “There is no question that NAT testing has reduced infections.”
The downfall to all of this is the cost. Both Drs. Chambers and Ness agree that the cost/benefit argument is one that plagues the industry. According to Dr. Chambers, it costs about $15 per donation to perform NAT.
“This is about $200 million a year country-wide to pick out a handful of HCV or HIV infected donors. So in two and a half years, it is about a half a billion dollars to prevent 50 or so disease transmissions in surviving patients,” Dr. Chambers comments. But this is something that they feel is worth the expense. And Dr. Chambers has high expectations for the test.
“The hope is that in the future, NAT testing will take the place of some of the serological testing or the p24 antigen testing for HIV,” Dr. Chambers comments. “Because as experience accumulates, we have not found any sample positive by p24 that was not also positive by NAT, so the p24 becomes redundant when that assay is in place.”
Universal Leukocyte Reduction
One of the other common ways to reduce transfusion-related illnesses is universal leukocyte reduction (ULR). According to the American Red Cross, removing leukocytes provides for a purer product and allows for fewer transfusion-related reactions.2 Concern over the potential adverse effects caused by the unnecessary transfusion of white blood cells that are concomitantly administered with therapeutic red cell and platelet transfusions has led to granting leuko-reduced blood products to only a select few, but this practice has caused a controversy throughout the health care industry.
According to Dr. Ness, most health care professionals are in agreement that leuko-reduced products are beneficial for patients that fall into these categories: those who have transfusion reactions due to white cells; those who are at risk of becoming alloimmunized and refractory to platelets; and those for whom it is beneficial to prevent the exposure of certain viruses such as cytomegalovirus (CMV). And Dr. Ness states that the panel is split concerning whether all people should have the benefit of leuko-reduced blood.
“My belief is that we should [have this available for all patients] because there are other risks that have not yet been identified that could be reduced by using leuko-reduced blood,” Dr. Ness explains. “Another reason is that even though our health care system recognizes that there are certain patients that fit the criteria, many will fall through the cracks.”
For example, those that are required to receive leuko-reduced blood are, in many cases, transfused in an emergency room before this information reaches the attending physician. So, in these instances, even the particular patient that has been allocated for leuko-reduced blood may not receive it.
Still, there are many controversies, including concerns for immunomodulation, which is especially important for patients undergoing a transfusion during surgery. Because the patients’ immune systems will be suppressed for some time following transfusion, they may be more at risk for contracting a wound infection. Dr. Ness explains there are debates, stating that by removing the white blood cells, this problem can be avoided. He does admit, though, that there are studies for and against this phenomenon.
The Red Cross has fully converted to prestorage leukoreduced blood. Whole blood derived, platelet concentrates and autologous units are not all leukoreduced, Dr. Chambers says, but all of the other red cells and platelets are.
Cost is yet another problem within this argument. According to Dr. Chambers, the cost for a leuko-reduced unit of blood is about $20 per component, which is comparable to what the country spends on NAT. So she believes that if there is a debate over the cost for ULR, there should be an equal debate over the cost of NAT.
“With NAT testing it is easy to say that we have prevented 20 infections, but with ULR undoubtedly we have prevented many more CMV transmissions and febrile reactions, some of which were destined to be severe,” Dr. Chambers adds.
On the Rise
According to the BaCon Study conducted by the American Association of Blood Banks, the American Red Cross, the Centers for Disease Control and Prevention (CDC) and the Department of Defense, it has been estimated that the bacterial contamination rate of red blood cells is as high as two-tenths of a percent and the rate of platelet contamination is as high as 10 percent. The study also reports that it is estimated that one of every 10,000 to 20,000 units transfused in the United States causes a febrile reaction due to contaminated blood.3
“It is well documented that bacterial contamination is the No. 1 cause of transfusion-transmitted infections,” says Barry Wenz, MD, medical director for PALL Corp. (East Hills, NY). “It is the No. 2 cause of all transfusion incidents reported and although all blood products are routinely screened for certain viruses, they are not screened for bacterial contamination of the blood product.”
These realities are what led PALL Corp. to contribute its part to defeating bacterial contamination like many other companies. PALL has submitted a 510K request to the FDA for permission to market its Bacterial Detection System (BDS).
“Being a filter company, the first thing we did was design a small filter that selectively removes the platelets and white cells from the sample aliquot that will be monitored, but allows the plasma that serves as a culture medium and bacteria, if present, to pass downstream of the filter. Following the filtration the amount of oxygen consumed as a function of bacterial concentration is measured,” Dr. Wenz explains. “What we are doing is taking out the background noise and increasing the sensitivity of the assay.”
It is with the platelet products that bacterial contamination is of the most concern. Because these products are stored at room temperature they encourage bacteria growth. For this primary reason, platelet products, which should have a shelf life of seven days, are discarded in five days, contributing to a large amount of expense.
PALL Corp. has tried to combat this problem with BDS. In fact, the company surveyed a series of recognized laboratories, which tested for the 10 organisms that account for 97 percent of the bacterial contaminations reported to the FDA during the past 24 years using BDS. According to Dr. Wenz, the laboratories all found that within 24-30 hours after taking the sample, 100 percent were detected with no false-positives.
“We believe that this will be a major advance in patient safety and we hope to accumulate sufficient data so that we can put the outdate of platelets back where it was originally, to seven days, and decrease expense to the user while doing so,” Dr. Wenz explains.
With all of the testing and detecting techniques available, the American Association of Blood Banks has deemed the blood supply the safest it has ever been.4 But no one has been complacent in trying to find the best way to keep blood safe for the public. Methods are now in development to inactivate pathogens and viruses that have entered the blood system.
Most pathogens contain DNA and/or RNA and techniques to inactivate them are based on this. Dr. Wenz explains that PALL, along with its partner VITEX Technologies (V.I. Technologies), is working on a technology embracing this idea. Their basis is a small molecular compound called the Pen 110, which concentrates on the red cells. It targets and reacts with certain residues on the DNA and/or RNA and once the molecule seeks out sites that have nucleic acid, it blocks the activity of the polymerases, which help the organism replicate. The self-activating compound becomes reactive only when it attaches to the negatively charged electrostatic binding sites within nucleic acids. Once activated, it forms irreversible covalent bonds with the nucleic acid.
Because of the vast majority of pathogens that are known and unknown, the FDA has preferred that pathogen inactivation be referred to as pathogen reduction, considering that there needs to be more research done to announce that all pathogens can be inactivated.
One form of pathogen reduction, solvent/detergent treated plasma (SD plasma), involves inactivating all viruses with lipid envelopes. SD plasma is designed to reduce the risk of viral transmission by fresh frozen plasma (FFP) that is already low in the infectious seronegative window period of currently screened viral infections, according to America’s Blood Centers. This reduces the risk of transmission of lipid enveloped viruses such as HIV-1, HIV-2, HCV and hepatitis B virus. SD plasma begins by pooling FFP. The pools are treated with solvent tri(N-butyl) phosphate and the detergent triton x-100 to disrupt the lipid envelope viruses.5
SD plasma has had some problems, though. Many are still using FFP because of its low risk of infectious disease transmission. In fact, according to Dr. Chambers, this country uses 90 percent FFP as opposed to 10 percent of SD plasma. She also explains that because SD plasma comes from pooled sources, many have shied away from using it. More importantly, Dr. Chambers says that since its introduction, there have been transmissions of parvovirus B19 in plasma that was SD treated. Although Dr. Chambers admits that this virus is not harmful to most of the population, it can have some adverse effects on selected patients such as those with HIV. To combat this problem, the plasma that is going to be used for SD plasma is first screened for parvovirus B19 and if it has a high titer, it is not used. There is also the issue of cost with SD plasma. It is about $15 more than a unit of non-SD plasma, notes Dr. Chambers.
However, the development of this technology has evolved yet another way to make blood products safer. What is coming next is a way to remove the anti-A and anti-B antibodies from the plasma product. The adverse reaction from isohemaglutinins has led researchers to look for a way to create a universal plasma product–one that can be used without regard for blood type. There is not yet a product to market, but the technology is promising.
“Taking out the isohemaglutinins levels out the playing field and all of the plasma becomes plasma equivalent suitable for transfusion without regard for the ABO of the recipient,” states Dr. Wenz. “In the point of view of supply and logistics, this would be an advance for the blood banking industry.”
The strides to make blood safer just keep coming and with the demand for blood, the timing couldn’t be better. According to Sam Wortham, president of the Medical Group of Companies at PALL, there are 4 million recipients of blood component transfusions in the United States and there are 18 million components transfused each year, a good reason to keep on top of all of the new technologies that are meant to keep patients safe.
In fact, Dr. Ness explains that the field is looking for alternatives to transfusions that can be put to use in certain situations. In fact, blood substitutes may become a solution that physicians consider. Although Dr. Ness admits that there are misconceptions about them, he feels that they could be useful.
Blood substitutes are short-term oxygen carrying capacity fluids, Dr. Chambers explains. These blood substitutes will be useful in trauma situations where patients need to be stabilized until they can be transferred to another hospital. Another important element of blood substitutes is that they can be kept on the shelf longer than regular blood components.
“Many of them are stable for years and some do not have to be refrigerated,” Dr. Chambers explains. “They are easy materials to stock for long periods of time.”
Once transfused, blood substitutes are only useful for a limited time, being cleared from the body in about 36 to 42 hours, says Wortham. However, there is no cross matching necessary and they are pathogen free.
Blood substitutes can in no way replace blood components because of the short-term characteristic. They will be especially important in emergency situations when patients need to be transfused immediately. However, if they are in need of more blood, a regular transfusion will take place.
Only one blood substitute has been approved and that is in South Africa. In April 2001, the American Red Cross announced that Biopure had been approved for their product Hemopure to be used in blood replacement of red cells during surgery.6
What Will Prevail?
Blood substitutes will not replace blood, but with all of the new methodologies that are up and coming, will something have to go? According to Wortham, most likely no testing techniques will be replaced. For instance, he does not believe that the introduction of NAT means the replacement of serological testing.
“If you look at the history of safety measures in blood banking, they have all been additives,” Wortham states. “So if history repeats itself, and that is expected, these [new techniques] will be additives and very few things will be replaced.”
Wortham is in agreement with Dr. Chambers, though, that it is possible with the success of NAT that the p24 surface antigen may be disregarded.
There are debates across the board about whether the other techniques will succeed. The ultimate goal is that there continues to be advances for the safety of patients. This will most definitely be expensive and time-consuming, but the alternative is more grave. In 30 years the country has gone from transfusing people with whole blood to the present, where a patient can receive individual components of blood, from very little sexually transmitted disease testing to a broad spectrum of blood analysis for this purpose. As the evidence presents itself, the future looks promising for the safety of blood products. n
Stephanie De Ritis is an assistant editor.
1. American Association of Blood Banks. Facts about blood and blood banking. Accessed: www.aabb.org/All_About_Blood/FAQs/aabb_faqs/htm#
2. American Red Cross. Universal leukocyte reduction Q&A. Accessed: www.redcross.org/services/biomed/blood/supply/ulr/qanda.html
3. BaCon Study. Frequency of bacterial contamination of blood components-2. Accessed: www.cdc.gov/ncidod/hip/bacon/indexAmerican
4. American Association of Blood Banks. AABB urges congress to support transfusion medicine research (Mintz): Testimony of Paul Mintz, MD on behalf of the American Association of Blood Banks–House Committee on appropriations. Subcommittee on labor, health and human services and education. Accessed: www.aabb.org/pressroom/in_ the_news/txresmintz032201.
5. America’s Blood Centers. Fresh frozen plasma: Two new Options. Vol.1, No.1 February 1998. Accessed: http://126.96.36.199/medical/bulletin_v1_n1.htm
6. Ornfinger, B. American Red Cross. South Africa approves first blood substitute. Accessed: www.redcross.org/news/bm/intl/010419sub.html.