Leukocyte-dependent vaso-occlusion was prevented in mice lacking both P- and E-selectins ( 3). Turhan and Frenette demonstrated that leukocytes mediate TNF-α–induced vaso-occlusion, which leads to reduced blood flow and death. Kaul and Hebbel showed that pathological stimuli, such as hypoxia-reoxygenation, resulted in decreased blood flow, enhanced leukocyte rolling, adhesion, emigration, and enhanced oxidant production, strongly supporting the concept that SCD is a disease of inflammation, oxidative stress, and reperfusion/injury physiology ( 9). Furthermore, these animal models mimic the pathology of human disease in response to stimuli, including hypoxia-reoxygenation, cytokines, LPS, and hemoglobin/heme ( 12– 14). SCD models have been developed with varying degrees of severity, exhibiting hemolytic anemia, leukocytosis, markers of inflammation, and activated coagulation. Transgenic mouse models of SCD have redefined the pathophysiology of vaso-occlusion. Of mice and men: murine SCD models tell a hot story Other cells have been implicated in sickle-associated vaso-occlusive events, including neutrophils ( 3, 4), monocytes ( 5, 6), platelets ( 4, 7), invariant NKT lymphocytes ( 8), and the endothelium itself ( 2, 9– 11). Patients with sickle cell disease (SCD) have marked leukocytosis, thrombocytosis, markers of inflammation, oxidative stress, and a procoagulant phenotype. As a result of this seminal observation, researchers in the 1980s and 1990s were able to define the red cell characteristics, endothelial adhesion molecules, and plasma factors responsible for these phenomena. The pain crises and organ infarctions that manifest in patients were attributed to a mechanical obstruction of blood flow due to the rigid crescent-shaped cells however, in 1980 Hebbel and others demonstrated that sickle erythrocytes were excessively adherent to vascular endothelial cells ( 2). Over the next century, evaluation of sickle cell anemia–associated molecular and cellular pathobiology revealed that the polymerization of hemoglobin S and cellular shape change upon deoxygenation were due to a single nucleotide mutation (A to T) in the gene encoding β-globin. In a 1910 report of an anemic West Indian man, Herrick first described the “peculiar elongated and sickle-shaped” rbcs produced by individuals with sickle cell anemia ( 1).

Misshapen blood cells