The first report of sickle cell disease was in a dental student from Grenada, Walter Clement Noel, who was studying in Chicago between 1904 and 1907. Dr. James Herrick and Dr. Ernest Irons were the first to identify the irreversibly sickled cells associated with his disease, described in their report as “very irregular, many elongated forms.” Noel later returned to Grenada to set up a dental practice and died at age 32 of acute chest syndrome. Neel and Beet described homozygous inheritance in 1947–1949. The demonstration of abnormal electrophoretic mobility of the hemoglobin S beta chain in subjects with sickle cell disease and trait led to the proposal by Pauling that this was a molecular disease of hemoglobin (1949), followed by the observation that valine had replaced glutamic acid on the beta globin chain (Ingram and Hunt, 1956–1958).
From a vascular biology standpoint, the observations of infarctions of the lung, kidney and spleen in the early 1930s, coupled with an understanding of the process of polymerization and sickling (Ham and Castle, 1940, among others) led to a hypothesis of a vicious cycle of increased vascular blood viscosity, determined by abnormal red blood cell rheology, hypoxia, more sickling and further increases in viscosity. An expanded understanding of the biophysical determinants of HbS polymerization (Eaton, Hofrichter, Noguchi, Schechter, and others) suggested that the polymers make the erythrocyte rigid, distort its shape, and cause structural damage to the red cell membrane, all of which alter the rheological properties of the erythrocyte, impair blood flow through the microvasculature, and lead to hemolysis and vaso-occlusive episodes. Accordingly, the rate and extent of hemoglobin S polymerization is the primary determinant of the severity of sickle cell disease, and the presence of fetal hemoglobin in the erythrocyte reduces the concentration of HbS and thereby interferes with its polymerization.
The concept of adhesive interactions between sickled erythrocytes and the endothelium was advanced in 1980 (Hebbel, Eaton and Steinberg), suggesting a link between the inflammatory nature of sickle cell disease and the microvascular pathogenesis. Recent studies in the microcirculation of transgenic mouse models of sickle cell disease confirm that hypoxic or inflammatory stimuli increase endothelial-leukocyte-erythrocyte adhesive interactions in the post-capillary venules, thereby initiating vascular occlusion. This model indicates that cycles of ischemia and reperfusion, in addition to intravascular hemolysis, cause oxidant stress, in which there is activation of vascular oxidases, and inflammatory stress, characterized by the expression of endothelial cell adhesion molecules, inflammatory cytokines, and leukocytosis.
On the heels of the discovery that the endothelium produces endothelium-derived relaxing factors, such as prostacyclin and nitric oxide (NO), much work has focused on the dysregulation of this pathway, particularly the development of progressive vasculopathy, characterized by systemic and pulmonary hypertension, endothelial dysfunction, and proliferative changes in the intima and smooth muscle of blood vessels. A hypothesis linking the process of hemolytic anemia with the release of plasma hemoglobin (Gladwin, Morris, Kato and others), which scavenges endothelium-derived NO, and arginase, which catabolizes arginine, brings the vascular biology of sickle cell disease full circle, from the modern discovery of NO to the earliest description of “hemolytic crisis” by Sydenstricker in 1924. New explorations of these pathways and the consideration of sickle cell disease as a progressive vasculopathy will now be discussed.
See the related ASH 50th Anniversary Review articles under the RED CELLS AND IRON section of the publication ASH 50th Anniversary Reviews: A Salute to the American Society of Hematology.