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

Abstract

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.

Keywords: Acute vaso-occlusive crisis; adhesion; blood flow; erythrocytes; leukocytes; sickle red blood cells.

Figure 1.

Proposed two-step mechanism for sickle red blood cell involvement in vaso-occlusive processes. Inflammatory mechanisms, caused by intravascular hemolysis and processes of ischemia-reperfusion, among other factors, lead to endothelial cell, leukocyte and platelet activation. Activated endothelium presents multiple adhesion molecules on its surface, including P-selectin, E-selectin and ICAM-1, which mediate cellular tethering to the vascular wall. Less-dense, deformable, less sickling-prone and more adhesive sickle red blood cells (SRBCs) are recruited to activated endothelium, as are activated leukocytes, especially neutrophils. In the microvasculature, especially venules, the mechanical obstruction of the vessel by the adhered SRBCs, and adhered leukocytes, increases the transit time of other SRBCs in the vessel, leading to the trapping of the denser sickling-prone SRBC population, as well as heterocellular aggregates, in these cellular agglomerates. Extensive cellular trapping associated with rheological alterations may result in local SRBC sickling, blood flow arrest and, therefore, vaso-occlusion. (A color version of this figure is available in the online journal.)