The Quest For Artificial Blood

Edna Fodor was enjoying a lazy summer evening at her son's cottage in Canada when the bonfire she was tending flared suddenly, searing her body from the waist up. Emergency rescue teams choppered her to Hamilton General Hospital in Ontario, where doctors would normally have cut away the burned skin to prevent infections, then grafted healthy skin to replace it. But such surgery involves extensive bleeding--and Fodor is a Jehovah's Witness, a member of a religious group that refuses blood transfusions. "We faced two deadly alternatives," says Dr. Brian Egier, director of the intensive-care unit. "We could either perform the surgery and have her bleed to death or let her die from the infections." Fortunately for Fodor, Egier was able to suggest a third option--so-called bloodless surgery using an experimental blood substitute called Hemolink. Although the product is not yet approved, Egier obtained an exemption for Fodor. Two years later she is happy, healthy and "lucky to be alive," she admits.

Hemolink is just one of a half-dozen blood substitutes that are nearing the market after decades of research. Known technically as "oxygen therapeutics," they aim to replace only oxygen-bearing red cells rather than whole blood with its additional plasma, platelets and infection-fighting white cells. Red cells are the most frequently transfused component of blood--tallying more than 12 million units a year--and the one that faces periodic shortfalls. Replacements could not only alleviate shortages, but also offer important advantages, including longer shelf life and compatibility with any blood type. "The minute they get approved, I'm going to be all over them," says Dr. Bruce Speiss, vice chair of anesthesiology at the Medical College of Virginia.

The history of transfusions has come a long way since the early 1800s, when Dr. James Blundell in England lost as many patients as he rescued with transfusions, since blood typing had not yet been discovered. "In the last century, transfusions have saved more lives than any therapy except antibiotics," says Dr. Harvey Klein, chief of transfusion medicine at the National Institutes of Health. But they have sometimes proved a mixed blessing. Two devastating bloodborne diseases--AIDS and hepatitis C--were unwittingly spread to tens of thousands of people by donor blood before the pathogens were identified. And although the U.S. blood supply is very safe today, says Karen Shoos Lipton, CEO of the American Association of Blood Banks, "we can only screen for diseases we know about."

Oxygen therapeutics could reduce the risks. These blood substitutes fall into two general types. The first is a synthetic chemical called a perfluorocarbon, or PFC, which would not risk contamination by bloodborne pathogens. The second type is based on actual hemoglobin extracted from discarded human or cow blood. The four companies in clinical trials with these products use stringent multistep processes to extract hemoglobin from red cells, then purify and stabilize it, so only hemoglobin is left. In theory, that should eliminate the possibility of disease transmission, whether of mad-cow disease from bovine hemoglobin or a suspected new strain of hepatitis from human products.

For practicality, oxygen therapeutics also excel. Banked blood lasts only 42 days, has to be refrigerated and must be cross-matched to patients to avoid negative reactions with incompatible blood types. But oxygen therapeutics last months to years at room temperatures and lack blood-typing proteins, which are found on the coats of red cells. "It's one size fits all," says chemist David Klein of Alliance Pharmaceutical Corp., which makes a PFC called Oxygent. That could make them particularly useful in ambulances, which cannot carry large stocks of refrigerated blood, and also on the battlefield. What's really intriguing about oxygen therapeutics, though, is that they appear to deliver oxygen to areas inaccessible to red blood cells. Both PFCs and hemoglobins are a fraction the size of a red cell. Early evidence--it remains to be proven in trials--is that they might slip past a clot that was causing a heart attack or stroke and deliver crucial air to oxygen-starved tissue.

PFCs present additional possibilities. Oxygent, the only such product in advanced trials, consists of tiny PFC molecules suspended in coated droplets. PFCs are slippery substances that easily shift around in the droplet, making space for oxygen molecules to move in or out, depending on the concentration of oxygen in surrounding tissues. Because all gases move from areas of high concentration to low, PFCs may prove useful in carrying other gases, too. "Heart-lung machines used in bypass surgery create tiny air bubbles in the bloodstream," says Speiss. "About a third of patients suffer permanently diminished mental function as a result." But Speiss says PFCs could absorb these bubbles, reducing neurological problems. Studies have yet to prove it. Meanwhile, the U.S. Navy is intrigued by the idea that Oxygent could treat the bends by absorbing dissolved nitrogen in the blood. Animal studies indicate it would.

There are downsides to oxygen therapeutics, though. PFCs cause a transient drop in platelet counts, while most of the hemoglobins cause a temporary increase in blood pressure. No one knows why these problems occur or whether they signal other complications yet to be discovered. Doctors are still learning how to use these products effectively. And since none of the substitutes lasts long in the body, they would not help patients who need chronic transfusions. Whatever their drawbacks or virtues, points out NIH's Klein, the most obvious limitation is that they are not yet on the market. Two hemoglobin-based products, Hemopure and PolyHeme, could achieve FDA approval by late 2003, but they will take years to gain widespread production and use. In the meantime, he says, the best way to fill the need for blood is for people to continue to donate.