Nitrite and Nitrite-Methemoglobin Therapy to Detoxify Stroma-Free Hemoglobin Based Blood Substitutes

Cell-free hemoglobin based oxygen carriers (HBOCs) are blood substitutes and resuscitative agents that can be used to replace whole blood donations, alleviate blood shortages and reduce the risks of infections such as HIV and hepatitis. Stroma-free HBOCs offer the advantages of increased stability, consistency of supply, and reduced immunogenicity over the use of the alternative cell based sources. However, the side effects associated with their use, including vascular toxicity, pulmonary and systemic hypertension, myocardial infarction, inflammation, and platelet aggregation severely limit their scope of clinical applications. These adverse effects are due in part to the ability of free deoxygenated hemoglobin (deoxyHb) to scavenge for nitric oxide (NO) thus rendering it unavailable for vasodilating blood vessels.

This technology is a method of using nitrites to reduce the deleterious effects associated with HBOC use as blood substitutes. Free nitrites or nitrite-methemoglobin when added to stroma-free HBOCs are converted to NO and N₂O₃ which escapes the scavenging activity of deoxyHb and thus is free to vasodilate blood vessels. This maintains oxygen release and NO delivery enabling improved clinical outcomes. Recent studies, using this technology as a blood substitute, have led to a reversal of vasoconstriction, hypertension and hemorrhagic shock in animal models. This new approach also reduces the toxicity associated with the use of HBOCs as a blood substitute and may allow the wide spread use of HBOCs as an alternative to cell based sources. In combination with this technology, HBOC blood substitutes may now be used to efficiently deliver therapeutic agents and maintain organ perfusion during trauma and surgery.