Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies

Abstract

Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin-reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review.

Figure 1

Sickle cell VOC. SS-RBCs and other inflammatory mediators induce the activation of the endothelium. The damaged and stimulated endothelium is poised to recruit leukocytes. E-selectin on the endothelium is crucial for generating a secondary wave of activating signals, which produces a polarized expression of activated αMβ2 integrin (Mac-1) at the leading edge of the crawling neutrophil, allowing the capture of circulating discoid and sickle-shaped erythrocytes. These events culminate in VOC in the postcapillary venules.

Figure 2

Activating and inhibitory arms of neutrophil activation. E-selectin–mediated adhesion activates Src kinases, which then leads to the up-regulation of the leukocyte integrin Mac-1 at the leading edge of crawling neutrophils. GMI-1070 works principally by inhibiting E-selectin–mediated activation. Polarized expression of activated Mac-1 allows the capture of erythrocytes. IVIG administration works by binding to FcγRIII expressed on neutrophils, leading to the recruitment of SHP-1 that inhibits Mac-1 activation.