The Ideal Blood Substitute: Probably Not in Our Lifetimes

May 1, 2002

BETHESDA, Maryland-The search for the ideal blood substitute continues, although with less urgency now that the nation’s blood supply is safer than it has ever been. None of the products currently being developed and nearing licensure can truly be considered substitutes for blood, according to Harvey Klein, MD.

BETHESDA, Maryland—The search for the ideal blood substitute continues, although with less urgency now that the nation’s blood supply is safer than it has ever been. None of the products currently being developed and nearing licensure can truly be considered substitutes for blood, according to Harvey Klein, MD.

Some of these products may, however, "have a niche use, particularly during surgery, where the endpoint will be to decrease or eliminate the use of allogeneic blood, but they are not going to replace either transfusion or recombinant human erythropoietin for a cancer patient during chemotherapy," he said.

"Nothing is going to replace blood, red blood cells, or erythropoietin in the near future."

Dr. Klein is chief, Transfusion Medicine, at the National Institutes of Health, in Bethesda, Maryland, and professor of medicine and pathology at the Johns Hopkins School of Medicine in Baltimore.

Safe Enough?

The risk of HIV infection through blood is one in every two million units of transfused blood. "The risk of hepatitis infection is also very low," Dr. Klein said, "probably less common than 1 in 180,000 units for hepatitis B, and now with direct assays for the virus, around 1 for every two million units transfused for hepatitis C."

"Blood is safer than it’s ever been before, but there remain a substantial number of complications," Dr. Klein noted. "One in every 12,000 units of blood in the United States is given to the wrong patient. I find that an astonishing statistic."

Blood can be infected by retrovirus variants that cannot be detected by the current screening tests. "So no matter how good our screening tests are, we will not be able to eliminate the risk of blood transfusion. And that’s the great safety paradox—blood is safer it has ever been, but safe doesn’t seem to be enough," Dr. Klein stated.

The Ideal Substitute

So-called blood substitutes are really not that at all, Dr. Klein noted, since they replace only one or possibly two functions of transfused blood—oxygen delivery and volume expansion. These products would be more accurately called red cell substitutes (RCS), Dr. Klein said.

The ideal RCS should: deliver oxygen, be nonantigenic, have zero infection risk (because the infection risk of the real thing is now so low), have a long shelf life, reconstitute easily, be able to circulate in the bloodstream for a long time, be nontoxic, and be inexpensive. "I can say to you without hesitation that I doubt that I will see that in my professional lifetime, if I see it in my lifetime. But we have a number of candidate substitutes that have some of these characteristics and some of them are pretty close to licensure."

Recombinant agents meet some of the characteristics of blood substitutes. Along with recombinant human erythropoietin (rHuEPO) there are recombinant forms of hemoglobin and of blood factor VIIa to replace clotting factors. Recombinant forms of factors VIII and IX "are very safe, but very expensive," Dr. Klein said. "Recombinant albumin is probably on the horizon," he added.

Three Substitute Classes

Although substitutes for red blood cells fall into three different classes, "every single compound that is going through clinical trials should be considered a different drug," Dr. Klein said. "They are different molecules; they are constituted differently; they have different biological and different chemical activities; and they are put in solutions that may have quite different characteristics."

The three classes are perfluorochemicals, hemoglobin-based oxygen carriers, and liposome-encapsulated hemoglobin.


Perfluorochemicals are synthetic halogenated hydrocarbons. They are inexpensive, inert and very stable, but not water insoluble, so they are mixtures or emulsions and sometimes the emulsifier is toxic, Dr. Klein noted. The perfluorochemicals "have low viscosity, which can be good," he said. "You can determine whatever half-life you want, depending on the particle size, but the tradeoff is toxicity—the smaller the particle size, the longer the half-life."

All of the perfluorochemicals now being tested cause mild thrombocytopenia a few days after the drug is administered and a 20% to 30% drop in circulating platelets. The reasons remain unknown. "Virtually all of the patients develop a flu-like syndrome, which is probably related to cytokine release," Dr. Klein noted.


Hemoglobin-based oxygen carriers (HBOCs) are made by chemically cross-linking the two alpha and two beta chains of hemoglobin or by recombinant technique. No recombinant HBOCs are currently in trials.

One HBOC has been licensed in the United States, but only for veterinary use. A human variety of this compound is being used in South Africa, "but there have been real concerns about renal toxicity, vascular hypertension, pulmonary hypertension, and peripheral hypertension," Dr. Klein reported.

HBOCs "are fundamentally different than red cells. They are very small molecules. They diffuse through the vessels and into the extravascular space to deliver oxygen, and they deliver it in a fundamentally different fashion…But we don’t really understand how," Dr. Klein said.

"The advantages of hemoglobin-based oxygen carriers are several," Dr. Klein reported. "They do have a high capacity for not only carrying oxygen, but carrying away carbon dioxide." They can be prepared to have either low or high viscosity.

One of the disadvantages is their very short half-life. "The half-life is measured in hours. So they’re not going to replace red cells and they are not going to replace erythropoietins. They could be used during surgery, but they are not going to be used for cancer patients during chemotherapy, at least not in their current form."

Liposome-Encapsulated Hemoglobin

Liposome-encapsulated hemoglobin has not realized the success of other liposome-encapsulated pharmaceuticals, according to Dr. Klein.