by Laurie J. Sutor, MD, MBA

The search for a viable alternative to banked human blood for transfusion has been ongoing for nearly 80 years. The ideal blood substitute would be cheaper, stored at room temperature, have a long shelf life, cause no adverse reactions, and be in plentiful supply. We would not have to worry about compatibility for blood types or transmission of infectious diseases. Unfortunately, this scenario remains a pipe dream despite millions of dollars spent over countless years of research.

Red cell substitutes have traditionally fallen into two types: hemoglobin solutions and perfluorochemicals. Hemoglobin solutions have enjoyed modestly more success and have gotten to phase III clinical trials in the U.S., but none have won FDA licensure and none are currently available for routine commercial use in this country.

Hemoglobin solutions could be made from human, animal or recombinant hemoglobin, but all have had various issues with toxicity, rapid clearing from the blood stream, and other adverse events. A 2008 meta-analysis by Natanson et al published in JAMA (299:2304-12) showed a significantly increased risk of death and myocardial infarction in patients getting hemoglobin solutions in an analysis of 16 clinical trials involving five different products. One of these products, Polyheme, made by Northfield Labs from human hemoglobin, had one of the more publicized later trials. Its 2006 clinical trial in trauma patients showed increased mortality in the group getting the red cell substitute. Following this disappointment, and a failed bid for FDA approval, Northfield Labs went out of business in 2009 after more than 20 years of effort on this product.

Another hemoglobin product, Hemopure, made from bovine hemoglobin, has been commercially available for human use in South Africa since 2006 for the treatment of surgical patients who are acutely anemic. It is also approved for commercial sale in Russia for anemia of any etiology. It is available in the U.S. only for investigational or expanded access/compassionate use. Oxyglobin, made by the same company (now called Hemoglobin Oxygen Therapeutics) is FDA and EU approved for veterinary use as a treatment for anemia in dogs. No other hemoglobin solutions are commercially available.

Work continues on the hemoglobin solutions, however, with additional studies planned, and hope persists that further work in cross-linking molecules and encapsulating the hemoglobin will help reduce the problems previously encountered.

The perfluorochemicals (PFCs) work by carrying oxygen in solution. The PFCs are inert and must be dissolved in plasma with an emulsifying agent. The amount of oxygen PFCs carry is proportional to the amount of oxygen to which they are exposed. These compounds have had less success and less attention over the years. Fluosol-DA was a first-generation PFC used in some Jehovah’s Witness patients. It had to be stored frozen and then administered with high levels of oxygen. FDA approved it in 1989, but its production ended in 1994 due to lack of use. Oxygent was a second-generation perfluorochemical that proceeded through phase III trials but was never FDA licensed.

The blood substitutes could serve an excellent niche for patients who cannot get traditional blood transfusion, or for transfusions occurring in austere or remote environments, where storage has its challenges. Although the flurry of activity that occurred in the last half of the twentieth century by many companies has abated in this area, work will likely continue on this front.