The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin

Abstract

Hemoglobin is a highly conserved molecule found in species ranging from single-cell organisms to mammals, but the role of hemoglobin in different organisms varies. While hemoglobin in bacteria functions as a nitric oxide sump by oxidation of nitric oxide to nitrate,^1-3 hemoglobin functions to remove oxygen in nematodes, a critical task for anaerobes.⁴ Quiz Ref ID By contrast, in mammals, hemoglobin primarily serves a respiratory function in the delivery of oxygen and removal of carbon dioxide. Based on the recent discovery that nitric oxide is a critical regulator of vasodilation and vascular homeostasis, the interactions of nitric oxide with hemoglobin in mammals has drawn increasing interest. Because the reaction of nitric oxide with the vast amounts of intravascular oxyhemoglobin (16 g/dL) is fast (10⁷ M^-1s⁻¹) and irreversible, it would be expected that nitric oxide produced by endothelium would be immediately scavenged by hemoglobin and would therefore be incapable of paracrine diffusion from endothelium to vascular smooth muscle.^5,6 However, the ability of hemoglobin to react with nitric oxide produced by endothelium is limited by compartmentalization of hemoglobin inside the erythrocyte.^7-9 Thus, the evolution of the erythrocyte may be considered as a mechanism of reducing toxicity while ensuring separation of the critical respiratory transport machinery needed for efficient oxygen delivery from the endothelium. Moreover, multiple systems have evolved to control the level of cell-free hemoglobin in the plasma during normal physiological hemolysis, presumably to curtail the deleterious effects of plasma hemoglobin on nitric oxide bioavailability and endothelial function.