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Red cell survival and NO scavenging in sickle cell disease

Nitric oxide (NO), a ubiquitous and versatile signaling molecule, reacts readily with both oxyand deoxyhemoglobin. During the first decade of this century, multiple experimental and clinical studies along with a number of review articles were published based on the hypothesis that NO depletion by elevated levels of plasma hemoglobin in the microcirculation plays a central role in the pathogenesis of sickle cell disease (SCD) [1–5]. These papers concluded that those patients with a relatively increased degree of hemolysis are at higher risk of developing pulmonary hypertension, leg ulcers, priapism, and perhaps stroke. The vast bulk of the data supporting these claims was based on indirect assessments of hemolysis by means of reticulocyte counts and measurements of serum LDH and bilirubin. The paper by Quinn et al. [6] that appears in this issue of the American Journal of Hematology provides critically important new information on red cell survival measurements in sickle cell patients that pertain directly to the role of hemolysis in the clinical manifestations of this disease. State of the art methodology involving the oral administration of a bolus of stable N-glycine followed by highly precise measurements of the mole fraction of this isotope in heme within circulating red cells has enabled the construction of highly accurate red cell survival curves. In some patients, a bi-phasic pattern provides a clear depiction of the contribution of the subpopulation of RBC that has relatively prolonged survival owing to the presence of Hb F. Although only 11 SS patients were studied, the data are so robust that firm and highly relevant conclusions can be drawn. The authors found that RBC survival was inversely correlated with reticulocyte count (P< 0.01) but was not significantly correlated with serum LDH, AST, and either total or non-conjugated bilirubin. Moreover measurements of tricuspid jet regurgitant velocity, a surrogate marker of pulmonary hypertension, correlated directly with serum LDH but not with red cell survival. The level of plasma hemoglobin is clearly the index of hemolysis most relevant to the proposal that NO scavenging by hemoglobin is responsible for certain complications of SCD. Clinical symptoms directly attributable to NO scavenging have been convincingly documented in patients with high levels of plasma hemoglobin. For example, about two thirds of those with paroxysmal nocturnal hemoglobinuria (PNH) have esophageal spasm with tightness of the chest and difficulty swallowing, particularly early in the morning and during hemolytic episodes. This symptom is completely eliminated by eculizumab, which causes a reduction in plasma hemoglobin to near normal levels [7]. As in PNH, NO scavenging is responsible for disordered GI motility encountered in patients receiving intravenous solutions of hemoglobin-based blood substitutes [8]. These gastro-intestinal symptoms are not encountered in patients with SCD.