In Search of a Blood Substitute
By Jamie Talan. STAFF WRITER
NOT EVEN the best minds in hematology have been able to design a liquid that can do a better job of delivering oxygen than the red blood cell can. But this reality hasn't stopped the search for the perfect blood substitute.
Human blood is the miraculous medium that ferries life-sustaining oxygen and nutrients throughout the body and transports carbon dioxide and other cell wastes out.
An artificial blood substitute would ease donor-blood shortages, eliminate the need to match blood types and ensure that donated blood is free of such harmful viruses as HIV.
A handful of companies is in the final stages of human testing of artificial blood products, and the U.S. Food and Drug Administration is preparing a consensus conference to be held in the next few months to discuss their safety and efficacy.
In the meantime, at this very moment dozens of people in clinical trials may be allowing their veins to be filled with solutions purified from cow's blood or genetically altered human blood cells. These products are generally called blood substitutes because they deliver oxygen throughout the body via plasma. Some scientists believe it may be possible to develop a product that could deliver oxygen more rapidly and efficiently than the unaltered red blood cell, but that is still very much in the "hope" category.
For now, these blood products are showing unique properties that could allow their use in lieu of fresh donor blood. The most important advantage is that they could be stored in the emergency room to provide an immediate supply of oxygen from the lungs to tissues, scientists say. Also, there is no need to type the blood because there are no immune antibodies to worry about. Also fueling the development of these products is the political fervor over tainted donor blood.
"The public is panicked about blood," said Dr. Joseph Fratantoni, a former FDA investigator who now works for the consulting firm C.L. Macintosh Co. in Rockville, Md. But despite the intensity of the search for a blood replacement, the results are emerging rather slowly. Even now, Fratantoni can't say whether there will ever be a federally approved blood replacement.
Just last month, Baxter Healthcare Corp. of Deerfield, Ill., ended a trauma-patient study after a review of the first 100 participants showed that people given the artificial blood product HemAssist died at a greater rate than those who did not receive it, said Mary Thomas, a Baxter spokeswoman.
Baxter had anticipated that 40 percent of the severely injured patients given HemAssist, a blood substitute modified from human red cells, could die. The company refused to give the exact number of patients who died or the exact number of those who received HemAssist, but Thomas did say that "about half" of the 100 were given the blood substitute and "slightly more than 40 percent" of those died.
The study, originally slated to include 850 patients, involved critically injured patients taken to hospital emergency rooms. These were among the most gravely ill trauma patients, and according to federal guidelines, only 3 percent of the nation's emergency room patients could be eligible for the study.
"This was really unforeseen," said Dr. Matthew Wall, director of Houston's Ben Taub Hospital's trauma center, where up to 40 patients were to participate this year. "This may simply be a statistical problem in a very select group of patients who already start with a high mortality, and the mortality may be unrelated to the drug."
The study was discontinued in Phase III testing, usually the last stage before such a product is considered for FDA approval. Studies of HemAssist in elective-surgery patients and severely injured patients in Europe are continuing because no abnormal mortality rates have been detected in those trials, Thomas said.
Fratantoni and others agree that analyzing the efficacy of artificial substances "has been a bear." "We don't even know how red blood cells work," said Fratantoni. "So how do you measure benefit?"
Hemoglobin is the stuff in red blood cells that carries oxygen from the lungs to the tissues throughout the body and shuttles carbon dioxide back to the lungs. The development of substances to ferry oxygen and mimic hemoglobin's job began decades ago.
The first artificial blood product was developed in 1965. Like red blood cells, all of these products pick up oxygen from the lungs and deliver it throughout the body. The first one worked in animals, and it was hoped it could work in humans. More than a decade later, in 1979, the first humans received infusions of Fluosol-DA, a suspension of clear, oily fluid (oil holds more oxygen than water).
The substance actually made it through years of doubt at the FDA, finally receiving approval for a very narrow indication: use in balloon angioplasty. But the technique was so cumbersome - it took an hour of prep time - that the company, Alpha Therapeutics Corp., stopped making it in 1993. It was on the market for only about four years.
The problem with hemoglobin, said Dr. Edward E. Jacobs, a senior vice president of medical affairs at BIOPURE, a Cambridge, Mass., company, and a surgeon at Massachusetts General, is that it's a fickle substance once it is taken out of the red blood cell. One of the pioneers in hemoglobin is Dr. Robert Winslow, who was hired in the early '80s by the Letterman Army Research Institute in San Francisco to develop a blood substitute. Winslow had done all sorts of nifty studies to get a handle on circulation, including spending laboratory time in the high altitude of the Andes to figure out how oxygen is transported by hemoglobin.
Winslow was able to purify hemoglobin, but when he and his colleagues infused it into animals, he noted some dangerous and troubling consequences. He soon realized there was a very good reason for the thick membrane that covered hemoglobin, protecting the substances within. "Without this membrane," said Fratantoni, "it was like walking around the blood vessels with a blowtorch."
There was a whole mess of reactions with the purified substance, he said. Some of the animals died. Many developed kidney damage.
Winslow and his colleagues demonstrated that it was hemoglobin alone that caused the toxic reaction in the animals. The molecule weighed 64,000 daltons (an atomic measurement) and consisted of four sub-units. Without the cell membrane, the hemoglobin simply fell apart. The kidney, the body's filter system, lets molecules through that weigh less than 64,000 daltons, and so the purified hemoglobin, without its protective coat, was damaging the kidney. Also, blood pressure skyrocketed.
It was agreed that scientists would have to figure out a way to keep the molecule together. Some companies made mixtures with chains of hemoglobin or connected it to a larger molecule so that it weighed more than 64,000 daltons. Some scientists, such as Dr. Thomas Chang at McGill University in Canada, worked on creating artificial membranes.
Red blood cells work best when fresh, but blood banks keep cells separated from donated blood for as long as 42 days. Donor blood can circulate for a month in the human body, giving the body time to replenish its own supply, and is then integrated into the body's blood supply. The first generation of blood substitutes lasted 27 hours.
The products now being designed circulate red blood cells for 120 days, Chang said. He wants to make a synthetic red blood cell rather than just chemically manipulate hemoglobin. In the laboratory, he takes hemoglobin and enzymes from the red blood cells, removes the membrane and wraps the material in an artificial coat. The packaging is about 16 times smaller than a red blood cell.
BIOPURE, the Cambridge company, has received FDA approval for Oxyglobin, the first blood substitute to treat anemia in animals. "This is amazing stuff," said Carl Rausch, BIOPURE chairman. "It's like fine wine."
Oxyglobin solution is now available to veterinarians for use in emergency situations, and the company has a similar "oxygen therapeutic," purified from the blood of cows, undergoing advanced clinical trials in humans. The substance is being tested in surgical situations, for critical-care interventions and for the treatment of sickle-cell anemia.
Jacobs developed the concept for Oxyglobin and designed both the animal and human studies necessary to match federal guidelines for safety and efficacy.
Jacobs says the BIOPURE substance "fundamentally changes the way oxygen is delivered to the tissues . . . You can show a relative potency of this material that is three times that of an equivalent amount of red blood cells."
Jacobs tells the story of one of the earliest experiments with this oxygen-carrying solution, in sheep. The animals were awake when blood was removed from their bodies and the artificial substance was pumped in in lieu of the real thing. Not only did they survive the exchange - they walked around - but they underwent anesthesia and a surgical procedure to remove a monitoring catheter, and, once awake, walked back into their cage. The substance worked long enough - about a week - for the animals to raise their own blood levels back to normal.
Oxyglobin is more than just a blood substitute, Jacobs adds. "This will be a very, very big change in how we view the circulation system. We could use this product to improve oxygen uptake in the lungs, and keep people with lung failure from having to go on a ventilator." Each year, 17 million people are in need of oxygen therapy, experts say. Ultimately, Jacobs envisions these blood substitutes, also referred to as oxygen substitutes, for use in blood clots, cancer, sepsis, damaged blood vessels and coronary artery problems.
Today, several different kinds of oxygen-carrying substances are being tested in humans. Northfield Laboratories Inc., a company in Evanston, Ill., buys units of human blood, removes the membranes and treats it with a chemical that joins the hemoglobin molecules together.
BIOPURE uses cow's blood to accomplish the same end. Baxter's product, which will continue to be used in European studies, has joined the four sub-units together so that they stay at the preferred weight of hemoglobin, 64,000 daltons. Another company called Enzon attaches it to a larger molecule. A number of other small companies are also in the race, with similar versions of these oxygen transporters.
Former U.S. Surgeon General C. Everett Koop says these substances have the "potential to revolutionize the practice of medicine, especially in critical-care situations." Koop now serves as a director at BIOPURE, in addition to many other roles. "When the history of 20th Century medicine is written, the development of oxygen therapeutics will be listed among the top 10 advances in medicine."
The FDA has developed extensive guidelines for these products - in terms of safety and efficacy - but it's been impossible to really know how beneficial the products will be. Fratantoni suspects the NIH consensus conference will address these issues and potential problems. Are the products safe? Effective? Easy to use?
Though some investigators believe that these blood substitutes will be useful for a variety of medical conditions - going far beyond the standard use for donor red blood cells - Fratantoni remains a healthy skeptic.
"If you are looking for something as good as red cells, you are not going to find it."
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