Creating an FDA-approved, synthetic replacement for human blood has so far eluded manufacturers. But because of its potential economic benefits, in addition to its compatibility with all human blood types, at least two companies remain determined to bring a blood substitute to market. While recognizing the value of a blood substitute, especially in emergency medical services, clinical laboratorians have voiced concerns about how such a product might interfere with diagnostic tests. This issue of Strategies examines how one lab in the midst of a clinical trial is dealing with interference issues and other ways synthetic blood might impact clinical laboratory testing.
In the pursuit of FDA approval for the first synthetic blood product, Evanston, Ill.-based Northfield Laboratories is currently conducting the PolyHeme Pivotal Phase III Study at 25–30 Level I trauma centers throughout the U.S. From results of the clinical trial, which is expected to have 720 patients enrolled, the company hopes to prove that the hemoglobin-based, oxygen-carrying product, PolyHeme, is well tolerated in a large patient population.
Long the focus of research and development efforts, blood substitutes offer compatibility with all blood types, lower manufacturing costs, and ease of transport and storage compared to human blood—all vital for trauma care such as emergency medical services, particularly in the military. In fact, earlier this month, Northfield Laboratories received $3.5 million in 2006 defense appropriation funding for the continued development of PolyHeme.
One of the trauma facilities participating in this clinical trial is LDS Hospital (LDSH) in Salt Lake City, Utah. Prior to the trial getting underway in early January, Northfield Laboratories presented the facility's clinical lab staff with extensive data on how their product behaved—or misbehaved—in tests at other labs. LDSH laboratorians then set about validating that data with their own instruments, explained Sarah Ilstrup, MD, the facility's Medical Director of Clinical Chemistry.
According to their studies, the LDSH laboratorians have determined that many of the typical tests run on trauma patients are not affected. Blood gas instruments are not impacted, nor are certain parts of the complete blood count (CBC) tests, including hemoglobin, the white blood cell count (WBC), mean corpuscular volume (MCV), red cell distribution width (RDW), and mean platelet volume (MPV) tests. However, although hematocrit determinations are unaffected, the blood substitute does affect the relationship between hematocrit and hemoglobin values. “The usual 3-to-1 hematocrit-hemoglobin relationship is lost in a PolyHeme patient,” said Ilstrup. “While most places in the country use hemoglobin concentration as a transfusion trigger, most of our physicians use hematocrit. We are concerned that physicians may order transfusions for a low hematocrit when the hemoglobin concentration is adequate due to Polyheme. So we are not going to report hematocrit on PolyHeme patients until they clear a significant amount of it and a more typical hematocrit:hemoglobin ratio is re-established.” For PolyHeme patients, laboratorians will probably suppress hematocrit values so there are no miscommunications to treating physicians. Other tests that appear unaffected include the CK-MB and troponin-I tests, although CK total and CK relative index are impacted once the PolyHeme level is > 2g/dL. There are some CBC components that are unreportable for PolyHeme patients, including mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC). Other tests are also impacted. “We saw an impact on results from our primary coagulation instrument: PT, PTT, and fibrinogen at all concentrations,” she explained. “Northfield told us that they didn't think these would be affected until a certain concentration of PolyHeme was present, but that wasn't our experience. Our plan will be to use a fibrometer for these tests. D-dimer has interference, also, and right now we are not sure what our back up will be.”
Other impacted tests include creatinine, although Northfield has showed the lab how to run creatinine on a filtered specimen, which produces results but increases turnaround time. Ilstrup and her colleagues have determined that liver function tests (LFTs) will also be impacted. “One of the biggest challenges we are going to face is that liver function tests are basically unreportable,” she explained. “Albumin, total protein, LDH, AST, ALT, GGT, and all bilirubin tests will be affected. We haven't found an alternative way to test for those yet.” She is also concerned that glucose meters will be impacted, and is awaiting data on these and other point-of-care tests.
Value to Search-and-Rescue
While the LDSH clinical lab has not encountered a PolyHeme patient yet, identification of the patient as a “PolyHeme patient” is a primary concern. If a specimen is processed and the lab doesn't know that the patient has been infused with PolyHeme prior to arrival, the initial response will be that the specimen is unusable or the patient has massive hemolysis. While rare, gross hemolysis does crop up in the LDSH lab. A few years ago, a child who died from rat bite fever presented with a massive hemolysis with a hematocrit of 18%. “If we don't know this is a PolyHeme patient, we will be calling to get a redraw, or initiating the massive hemolysis differential,” said Ilstrup. “The process is that the specimens are supposed to arrive with stickers that clearly indicate these are from a PolyHeme patient. We believe we can get a reasonable estimate of the PolyHeme concentration from plasma specimens run on our hematology analyzer. In the event we suspect a patient is on Polyheme, based on an atypical hematocrit:hemoglobin ratio and chemistry specimens that appear hemolyzed, we will contact the patient care unit or the PolyHeme study coordinator to see if the patient received PolyHeme.”
Despite some of the interference issues, Ilstrup is clear about the potential benefits of having a product like PolyHeme available to emergency medical crews. In the Salt Lake City region, many residents take advantage of the mountainous environment and are active in outdoor pursuits such as hiking and skiing. This means, however, that a lot of the accidents related to these activities demand that search-and-rescue workers go up mountains or into canyons. “Although Intermountain Life Flight is the only civilian air rescue operation that is approved by the Federal Aviation Administration for high altitude hoist operations of patients, bad weather and night operations may preclude the use of helicopter hoist operations,” she explained. “Instead of an air ambulance pulling up to an accident or disaster site, it's a search-and-rescue team running three hours into a canyon and hiking back out with a victim. This kind of a product could be great in these situations.”
But PolyHeme presents another challenge in terms of organ donation when synthetic blood recipients die. Trauma patients often die from significant head injuries, even though many of their organs are intact and ideal for transplants. “If a patient dies and they are a designated organ donor, they may not be able to donate because the lab can't get reliable serology readings when patients who receive the synthetic blood expire,” explained Ilstrup. Serologies are virtually untestable until the PolyHeme is cleared through the liver and spleen, which often takes between 24–72 hours, at which time the organ may no longer be viable. The LDSH laboratorians are working with the EMS and trauma services to draw pilot tubes for PolyHeme patients, before the patient receives the blood substitute. This could allow the victims to still be donors, which is often important to their families. “We would hate to eliminate a potentially good donor, because the donation salvages something good for families out of a terrible situation,” Ilstrup explained.
Other Synthetic Blood Makers
Another manufacturer seeking regulatory approval of synthetic blood is HemoBioTech Inc. (Dallas, Texas), whose product HemoTech has undergone some clinical trials overseas. Company officials are speaking with the FDA about beginning Phase I clinical trials this year in the U.S. This product is different from other products that have failed to get approval because the hemoglobin is combined with adenosine and reduced glutathione, which makes it vasodilatory and anti-inflammatory, according to Arthur Bollon, PhD, Chairman and CEO of HemoBioTech. In addition, HemoTech induces erythroporesis—the production of new red blood cells to carry more oxygen throughout the body.
Bollon declined to comment on the potential interference between HemoTech and laboratory testing, stating that the issue was currently under investigation. However, he did indicate that given the potential value of this product, it might be necessary for lab tests to make adjustments to accommodate the HemoTech, rather than the product adjusting to laboratory testing. “If our product continues to show the same results in additional studies, such as being nontoxic, inducing erythroporesis, being anti-inflammatory, and being an oxygen carrier, any professional in the medical field would realize the benefits of such a product to the patient,” said Bollon. “I would think that a product of that importance would simply require whatever adjustments one has to make in testing, because the benefits would greatly outweigh any additional improvements in testing.”
Since HemoTech is slated to begin clinical trials this year, it will likely not be commercially available until 2009, depending on the pace of the regulatory approval process. Northfield Laboratories officials declined to comment on their product, but indicated enrollment for the PolyHeme clinical trial should be concluded this spring. Therefore, PolyHeme will likely not receive a decision from the FDA until late 2007 or early 2008.
Julie McDowell is the Editor of Strategies. She can be reached by email.