HEMOGLOBIN BASED OXYGEN CARRIERS AT A CROSS ROAD: THE OLD PARADIGMS MUST BE ABANDONED AND MUCH MORE BASIC SCIENCE INVESTIGATION IS NECESSARY

Research on “blood substitutes” started near the end of WorldWar II when the military were impressed by the number of casualties with consequent need of blood transfusions. Unfortunately at that time this field was shunned by academia as an inferior kind of applied research, moreover marred by the sadness of war.

Thus the research was started by a group of courageous and dedicated pioneers who, challenged by the multidisciplinary nature of the endeavor and irrespective of their original background, had to improvise themselves simultaneously as chemists, protein chemists, physiologists, biochemists, surgeons, physicians, hematologists, blood bankers, hemoglobinologists. It was an overwhelming task, softened by the ideas that anything capable of exchanging molecular oxygen could be used as blood replacement. At that time the only available criterion for the viability of the various compounds was survival versus non-survival of infused animals. Also the conventional wisdom and present FDA requirements were and are that “blood substitutes” should have oxygen binding characteristics similar to those of blood.

Based on these criteria, very soon it appeared that the goal of obtaining a “blood substitute” was not easy. Thus the work was distributed into many different approaches including: intramolecularly crosslinked hemoglobins, polyhemoglobins, recombinant hemoglobins, conjugated hemoglobins, encapsulated hemoglobins.

Academia became interested, and private concerns started developing substitutes, lured by a potentially unlimited market. Thus, after 50 years of efforts full of ups and downs with academic laboratories starting and ending their research and private concerns oscillating between venture capital investments and bankruptcy, only three polyhemoglobins survive in the phase III clinical trails namely Polyheme (human Hb polymerized with glutaraldehyde, Northfield, Deerfield, IL), Biopure (bovine Hb polymerized with glutaraldehyde, Biopure, Boston, MA), Hemolink (raffinose polymerized human UB, Hemosol, Toronto, Canada). The clinical trials with Optro (a recombinant hemoglobin, Somatogen, Boulder, CO) and Hemassist (an intramolecularly crosslinked hemoglobin, Baxter, IL) were suspended. It may be noticed that all surviving products are from small private concerns. In fact, after an initial enthusiasm, Federal Agencies like NIH and DOD lost interest in supporting independent laboratories.

This is unfortunate, because the inevitable corporate policies of investments and confidentialities prevent small companies to develop new products and ideas. Their activity is locked into old technologies developed 15–30 years ago. The consequence is that at a recent FDA workshop in Bethesda, MD (Sept 1999) the representative of the three companies mentioned above confessed that the criterion for viability of their product is still the survival/not-survival of the prepositi (this time humans). They could not offer anything better to those who loudly objected.

These old ideas and technologies have been challenged. Recombinant hemoglobins are continuously produced (see in the web under Clara Fronticelli, John S. Olson and Chen Ho), new chemistry is produced in the laboratory of this author [1-2] and of Dr. Thomas Chang [[3]], new encapsulations are proposed [4-6]. Absorption of NO as cause of increasing mean arterial pressure (MAP), produced by most of the modified hemoglobins, is also very confusing. The old proposal that it is due to scavenging of NO by the cell free hemes is very reasonable and supported by experimental evidences. However it is not consistent with recent data obtained by Winslow [[7]] and Intaglietta [[8]]. The last authors report that the size of the arterioles of rat mesentery is inversely proportional to the diameter of the infused hemoglobins. The cause of this correlation is not clear. The author of this editorial reports that tetrameric hemoglobins (that notoriously increase MAP) extravasate and appear in the lymph, even if they do not appear in the urine. Instead large polymeric hemoglobins do not extravasate and have little effect on MAP [[9]]. Absorption of NO may not be the sole cause of the phenomenon. There are indications that there is a synergistic effect on oxygen diffusion from artificial capillaries when red cells are mixed with cell free hemoglobin [10-11]. On this and other evidences Vandegriff and Winslow challenge the conventional wisdom that the substitutes should have characteristics similar to blood. It is proposed that high oxygen affinity compounds would be better carriers than low affinity ones [[12]].

It appears that cell free oxygen carriers, even those based on hemoglobin, are not “blood substitutes” whose characteristics should be compared to those of blood. They are new oxygen carrying compounds with their peculiar mechanism of oxygen transport in vivo. The negative experience of Baxter on trauma patients [[13]] testifies to the need of learning this new physiology before designing clinical trials. At the FDA workshop in Bethesda, the reported success of blood replacement in hemorrhagic patients, based on the empirical survival/non-survival approach, only shows that they can be beneficial, as expected. This is the crossroad mentioned in the title of this editorial. The old paradigms that cell free oxygen carriers must have characteristics similar to blood are not tenable and, if enforced by either FDA requirements or NIH study sessions, prevent developments. There is much need to study in depth the rheology and viscosity effects in vivo of the infused carriers, their extravasation properties and, most important, the physiology and mechanism of cell free oxygen transport.