Sickle cell vaso-occlusion: The dialectic between red cells and white cells.

The pathophysiology of sickle cell anemia, a hereditary hemoglobinopathy, has fascinated clinicians and scientists alike since its description over 100 years ago. A single gene mutation in the HBB gene results in the production of abnormal hemoglobin (Hb) S, whose polymerization when deoxygenated alters the physiochemical properties of red blood cells, in turn triggering pan-cellular activation and pathological mechanisms that include hemolysis, vaso-occlusion, and ischemia-reperfusion to result in the varied and severe complications of the disease. Now widely regarded as an inflammatory disease, in recent years attention has included the role of leukocytes in vaso-occlusive processes in view of the part that these cells play in innate immune processes, their inherent ability to adhere to the endothelium when activated, and their sheer physical and potentially obstructive size. Here, we consider the role of sickle red blood cell populations in elucidating the importance of adhesion vis-a-vis polymerization in vaso-occlusion, review the direct adhesion of sickle red cells to the endothelium in vaso-occlusive processes, and discuss how red cell- and leukocyte-centered mechanisms are not mutually exclusive. Given the initial clinical success of crizanlizumab, a specific anti-P selectin therapy, we suggest that it is appropriate to take a holistic approach to understanding and exploring the complexity of vaso-occlusive mechanisms and the adhesive roles of the varied cell types, including endothelial cells, platelets, leukocytes, and red blood cells.

Production of F cells in sickle cell anemia: regulation by a genetic locus or loci separate from the beta-globin gene cluster

Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2 percent to 50 percent in patients with sickle cell (SS) anemia. To learn whether any portion of such variation in F cell production is regulated by loci genetically separable from the á- globin gene cluster, percentages of F reticulocytes were compared in 59 sib pairs composed solely of SS members, including 40 pairs from Jamaica and 19 from the United States. We reasoned that differences in F reticulocyte levels might arise (1) from any of several kinds of artifact, (2) via half-sib status, or (3) because one or more genes regulating F cell production segregate separately from ás. We minimized the role of artifact by assay of fresh samples from 84 SS individuals, including both members of 38 sib pairs. In 78 of the 84 subjects, serial values for percent F reticulocytes fell within 99.9 percent confidence limits or were alike by t test (Po .05). This left 32 sib pairs for which F reticulocyte levels in each member were reproducible. When sib-sib comparisons were limited to these 32 pairs, percentages of F reticulocytes were grossly dissimilar within 12 Jamaican and 3 American sibships. Within them, the probability that sibs were alike was always ó .005 and usually ó 10 to the 4th power. We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib-sib comparison of á-globin region DNA restriction fragment length polymorphisms, especially among discordant pairs. We thereafter concluded that at least seven to eight Jamaican pairs were composed of reproducibly discordant full sibs. There is thus little doubt that there are genes regulating between-patient differences in F cell production that are separate from the á-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to á to the s power, (2) why F reticulocyte levels in Americans tend to be lower than in Jamaicans, and (3) whether or not differences in F cell production among SS patients are regulated by several major loci or by only one (AU)