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Overview

The polymerization of deoxygenated sickle hemoglobin provides the elemental basis for the pathophysiology of sickle cell anemia (SCA). Nonetheless, this disease still presents abundant uncertainties and mysteries, something particularly true for events involved in the occurrence, resolution, and consequences of sickle vaso-occlusion.1 This chapter will describe the unique character of ischemia-reperfusion (I/R) pathophysiology occurring in SCA and why it likely plays a pivotal role in its pathophysiology. Indeed, some features of SCA are less easily explained, in particular the perpetuity, intensity, systematicity, complexity, and instability of its unique inflammatory state.2-4

Thus, we perceive I/R pathobiology to be the foundational engine that relentlessly drives inflammation because, in the specific sickle context, it establishes an inherent cyclicity (Figure 6-1). This would be the modern realization of the “vicious cycle” between erythrostasis and sickling/hemolysis posited by Ham and Castle in 1942. It is a context that reveals both the robust adaptability of human biology and its exquisite vulnerabilities.

FIGURE 6-1

Ischemia-reperfusion pathobiology in sickle cell anemia. Ischemia-reperfusion cyclicity is the foundational engine that drives the inflammatory state, explaining its perpetuity, complexity, intensity, systematicity, and instability. The boxes indicate a few of the major actors. The result is a constant activating influence, causing blood cell adhesion to endothelium and thus slowing microvascular transit of red blood cells (RBCs) and enabling sickling and vaso-occlusion. DeoxyHbS, deoxygenated hemoglobin S; EC, endothelial cell; eNOS, endothelial nitric oxide synthase; Hb, hemoglobin; HbS, hemoglobin S; HMGB1, high mobility group box 1; IL-1β, interleukin-1β; NF-κB, nuclear factor-κB; O2, oxygen; PLT, platelet; PO2, partial pressure of oxygen; TNF, tumor necrosis factor; WBC, white blood cell. Modified, with permission, from Figure 1 of Hebbel RP, Elion J, Kutlar A. The missing middle of sickle therapeutics: multi-agent therapy, targeting risk, using biomarkers. Am J Hematol. 2018;93(12):1439-1443.

Understanding I/R in SCA requires cognizance of the literature on experimental I/R and the human I/R-related diseases generally, the studies of sickle transgenic mice and humans with SCA, and the pathobiologies of the general medical analogs of SCA complications. Assembly of this puzzle illuminates the role that I/R likely plays in the vascular wall dysfunction and, therefore, clinical phenotype of SCA.

In focusing on I/R in the sickle context, we certainly do not argue that hemolysis is of no consequence. Indeed, sickle red cell hemolysis releases multiple agents that present danger to endothelium, including microparticles, cell-free hemoglobin and heme, procoagulant lipid, and arginase.5 Such factors contribute to the sickle inflammatory state (Figure 6-1).

General Introduction to I/R

Fundamentally, I/R is the biology of resolving ischemia, the concept being that the reintroduction of oxygen to an ischemic area can, paradoxically, exacerbate local tissue injury. I/R thereby differs from the pathobiologies of simple hypoxia or infarction. Although ...

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