The multifaceted role of ischemia/reperfusion in sickle cell anemia

Abstract

Sickle cell anemia is a unique disease dominated by hemolytic anemia and vaso-occlusive events. The latter trigger a version of ischemia/reperfusion (I/R) pathobiology that is singular in its origin, cyclicity, complexity, instability, perpetuity, and breadth of clinical consequences. Specific clinical features are probably attributable to local I/R injury (e.g., stroke syndromes) or remote organ injury (e.g., acute chest syndrome) or the systematization of inflammation (e.g., multifocal arteriopathy). Indeed, by fashioning an underlying template of endothelial dysfunction and vulnerability, the robust inflammatory systematization no doubt contributes to all sickle pathology. In this Review, we highlight I/R-targeting therapeutics shown to improve microvascular blood flow in sickle transgenic mice undergoing I/R, and we suggest how such insights might be translated into human therapeutic strategies.

Figure 1. The pathophysiology of sickle cell anemia is cyclic, with a robust inflammatory state that is driven by blood cell adhesion to endothelium, leading to I/R.

Figure 2. Biological convergence of heme and HMGB1 as inflammatory instigators.

Activation of TLR4 leads to the secretion of Weibel-Palade bodies as well as proadhesive and procoagulant phenotypes in vascular endothelial cells.

Figure 3. Key early features of I/R in the sickle context.

(A) Compared with normal, baseline sickle vascular biology includes somewhat increased adhesion molecule expression, some baseline rolling of red cells and leukocytes on endothelium, and increased flow rate. Sickle vaso-occlusion is triggered by red cell and/or leukocyte adhesion in postcapillary venules, resulting in retrograde sickling and obstruction. Upon reperfusion, adhesion molecule expression and blood cell rolling and adhesion are far more prominent, the glycocalyx has thinned, and flow is notably hyperemic. (B) An expanded view of the reperfusion in A, showing prominent early pathobiology of local I/R injury in SCA.