TY - CHAP M1 - Book, Section TI - Hemolysis and Endothelial Dysfunction A1 - Kato, Gregory J. A1 - Gladwin, Mark T. A2 - Gladwin, Mark T. A2 - Kato, Gregory J. A2 - Novelli, Enrico M. PY - 2021 T2 - Sickle Cell Disease AB - 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. SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/03/28 UR - hemonc.mhmedical.com/content.aspx?aid=1179338153 ER -