Basic science focus on blood substitutes: a summary of the NHLBI Division of Blood Diseases and Resources Working Group Workshop, March 1, 2006

Abstract

In March 2006, a workshop sponsored by the National Heart, Lung, and Blood Institute was convened to identify the role of basic science research in clarifying issues that are impeding progress in the development of hemoglobin-based oxygen carrying (HBOC) solutions. These discussions resulted in a consensus that, although HBOCs have shown clinical promise, various side effects have inhibited further development and regulatory approval, with cardiovascular events being of particular concern. As a consequence, workshop participants focused on formulating research recommendations to better understand and mitigate these side effects. In addition, several important corollary issues were identified, including better understanding of the impact of HBOC infusion on human physiology; the need for rapid, noninvasive methods for the measurement of tissue oxygenation in human patients to better inform transfusion decisions; further investigation of routes and consequences of hemoglobin metabolism; optimization of clinical protocols for HBOC use; and assessment of the impact of HBOC formulation excipients. Also discussed was the possibility and desirability of developing new HBOCs with improved characteristics, such as prolonged functional intravascular persistence, greater stability, and a decreased propensity to generate reactive oxygen species. One practical limitation in this area is the consistent availability of pure, well-characterized HBOC solutions for the research community. This communication summarizes the opinion of workshop participants on these issues and concludes with a list of specific recommended areas of research that could positively impact the development of blood substitutes.

Development of Recombinant Hemoglobin-Based Oxygen Carriers

“…These detrimental properties of the TrpE7 and TrpE11 mutations probably account for the unsuccessful initial human safety trials of rHb2.0 that was based on the rHb3011 design. The oxidative stress and inflammation resulting from plasma Hb denaturation seem a likely cause of complement activation, although this conclusion needs further testing (40). Regardless, it is clear that alternative strategies are needed for lowering NO scavenging while retaining low rates of autooxidation, hemin loss, and globin unfolding.…”

“…The rHb3011 molecule has also been shown to reduce or prevent gastrointestinal dysmotility (54), and its genetic background was built into the last Baxter HBOC prototype, rHb2.0, which also showed no hypertensive side effect (56,84,110,116,142,155). However, rHb2.0 was later shown to cause complement activation in initial safety trials in humans (40), which, as shown in Figure 5, appears to be due to high rates of autooxidation, hemin loss, and/or globin denaturation, properties that were not optimized in the second-generation product, but have been shown to lead to endothelial damage and inflammatory responses (8-10).…”

“…Both types of products can be transfused in place of packed red blood cells to restore impaired oxygen transport and offer the following advantages: (i) universal compatibility; (ii) longer shelf-life; (iii) diminished risk of disease transmission; (iv) enhanced oxygen delivery; (v) improved rheological properties; (vi) improved uniformity in composition; (vii) more reliable availability; and (viii) use by individuals who cannot receive conventional blood transfusions for clinical, geographical, or religious reasons (55,88,94,143,147). Despite these advantages, significant efforts at developing HBOCs and rHBOCs have not yet resulted in therapeutic licensure in the United States, although HBOC 201 (HemopureÔ; OPK Biotech, Boston, MA) is approved for human use in South Africa and Russia (40,72). The lack of approval of these HBOC products in the United States is primarily due to reports of adverse cardiovascular and cerebrovascular events associated with hypertension (4,18,26,40,44,55,64,65,72,74,81,88,94,105,138,143).…”

“…Despite these advantages, significant efforts at developing HBOCs and rHBOCs have not yet resulted in therapeutic licensure in the United States, although HBOC 201 (HemopureÔ; OPK Biotech, Boston, MA) is approved for human use in South Africa and Russia (40,72). The lack of approval of these HBOC products in the United States is primarily due to reports of adverse cardiovascular and cerebrovascular events associated with hypertension (4,18,26,40,44,55,64,65,72,74,81,88,94,105,138,143). In the case of recombinant HBOCs, additional barriers to development include globin denaturation, misfolding, and heme-orientational disorder, issues that arise during expression of recombinant heme proteins (46,108).…”

Blood Substitutes

“…Indeed, essential paradigms regarding oxygen delivery (e.g., impact of low oxygen affinity and low viscosity) have recently been challenged by the innovative design of Hemospan™, indicating that a better understanding of oxygen delivery at the site of microcirculation and oxygenation of tissues, cellular, and subcellular structures may be required for an appropriate efficacy-assessment of OCBS. To this end, most target parameters may predominantly be assessed in experimental models, and these experiments should be predictive of response in humans, incorporate stress conditions, and be used to systematically evaluate the effect of variation of Hb structure, biochemistry, and physical chemical properties [23].…”