Paradigm Shift for Designing Oxygen Therapeutics: New Insights Emerging from Studies with Transgenic Mouse Models of Sickle Cell Disease: Synergy of Supra Plasma Expansion and High O₂ Affinity of Blood Substitutes

The design of EAF P5K6 Hb at Einstein represents a major paradigm shift in designing oxygen therapeutics: (i) use of high oxygen affinity Hb instead of low oxygen affinity Hb to target the oxygen delivery to hypoxic areas and attenuate an early release of oxygen on the arterial side (ii) induce colloidal plasma expander like activity to Hb to off-set the vasoconstrictive activity intrinsic to anemia and induced by reduced viscosity due to reduced hematocrit levels. MP4, a prototype of EAF P5K6 Hb generated by Sangart, is a high oxygen affinity Hb, non-hypertensive, and a vasodilator. The viscosity of a 4 gm % solution of MP4 is comparable to that of conventional colloidal plasma expanders, but its microcirculatory parameters are like those of supra plasma expanders, i.e., plasma expanders with a viscosity comparable to blood or higher. However, MP4 did not oxygenate tissues better than non-oxygen carrying supra plasma expanders in extreme hemodilution. MP4, surprisingly, seems to facilitate extraction of more oxygen from RBC and this leads to a lower venous PO2 than control. On the other hand, di-PEGylated Hbs, P5K2 Hb and P10K2 Hb, oxygenates tissues in extreme hemodilution much better than MP4. EAF P3K6 Hb, has been designed to engineer a smaller PEG-shell to map the role of PEG-shell in tissue oxygenation. This molecule did better than MP4, thereby demonstrating that the pattern of PEGylation dictates the efficacy of tissue oxygenation. The improvement in tissue oxygenation has been accomplished without inducing lowering of venous P02. EAF P3K6 Hb exhibits excellent SCD therapeutic activity in transgenic sickle mice including the clearing of vaso-occlusion, normalization of high Cerebral Blood Flow (CBF) in brain in Berk. Normalization of CBF is achieved without a major increase in oxygen carrying capacity even though these animals were very anemic. A new concept has emerged here, EAF P3K6 Hb facilitates in-flow of oxygen into RBC in lungs (increased oxygen saturation) and out-flow of oxygen from RBC into tissues during anemia (increased tissue oxygenation) in a catalytic fashion. EAF P3K6 Hb is a “nano oxygen pump”. The release of more oxygen from RBC in the presence of “nano oxygen pump” in plasma accomplishes targeted release of vasodilator, NO, to improve perfusion. High oxygen affinity PEG Hbs, a new class of oxygen therapeutics, will be useful in critical care medicine as an alternate to oxygen therapy as well as in combination with oxygen therapy.