Sickle cell anemia (SCA) is characterized by severe chronic hemolysis that gives rise to anemia. There are many pathophysiologic responses to the hemolysis and to its resulting anemia. Most of these responses are adaptive in the short term, but some of these can have maladaptive consequences in the long term. The most harmful form of hemolysis is intravascular hemolysis, which releases the contents of red blood cells directly into plasma. Cell-free hemoglobin, free heme, arginase, and methylated arginines reduce nitric oxide (NO) bioavailability and promote oxidative stress and inflammation. Cell-free hemoglobin scavenges NO in a rapid, nearly diffusion-limited dioxygenase reaction. Both cell-free hemoglobin and free heme promote intense oxidative stress and serve as damage-associated molecular patterns (DAMPs). This activates the innate immune system to produce inflammatory cytokines, promoting adhesion molecule expression on blood cells and endothelial cells. Multilayered adaptive mechanisms have evolved to clear hemoglobin and heme, including haptoglobin and hemopexin. However, the severe chronic hemolysis in SCD saturates the haptoglobin system and depletes both haptoglobin and hemopexin. Arginase and methylarginine limit the activity of NO synthase to increase NO production to compensate for the destruction of NO. The physiologic consequences of decreased NO bioavailability include chronic vasoconstriction, proliferative arteriopathy, and increased platelet aggregation and clotting, especially in the pulmonary vasculature. Severe anemia results in high erythropoietin secretion, with increased circulating placenta growth factor (PlGF) and endothelin-1, a potent vasoconstrictor. Severe anemia also induces red cell content of 2,3-diphosphoglycerate (2,3-DPG), which lowers oxygen affinity and basal oxygen saturation and promotes HbS polymerization. Severe hemolytic anemia increases the risk of gallstones, systemic and pulmonary hypertension, leg ulceration, priapism, nephropathy, and stroke.
Historical Aspects of Hemolysis in Sickle Cell Disease
In the first case report of SCA in the English language, Herrick1 reported anemia as a feature but did not elaborate on its possible mechanism. In 1923, Sydenstricker et al2 reported 2 children with SCA, including the first reported necropsy. They observed that “yellow sclerae,” “bile in the urine,” and “brown granules in the Kuppfer cells of the liver and in the epithelium of the kidney tubules … suggest most strongly that there is a hemolytic factor in the production of the anemia.” We would recognize this description today as (1) scleral icterus from indirect hyperbilirubinemia, the result of increased heme turnover; (2) increased urinary excretion of bilirubin; (3) possibly hemoglobinuria due to intravascular hemolysis exceeding the renal threshold for hemoglobin reabsorption; and (4) accumulation of iron as hemosiderin in the macrophages of the liver and the epithelium of the renal tubules. These are all well-established indicators of the extensive chronic extravascular and intravascular hemolysis that will be the focus of this chapter. By 1924, several authors alluded to the deduced role of hemolysis in SCA.
William Crosby was an influential figure in hematology in the 1950s and 1960s. He served as director of the Division of Medicine at Walter ...