Pathophysiology of Sickle Cell Disease.

Pathophysiology of Sickle Cell Disease.
Annu Rev Pathol. 2018 Oct 17;:
Authors: Sundd P, Gladwin MT, Novelli EM
Abstract
Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the β-globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD, manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to endorgan ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: (a) hemoglobin S polymerization, (b) impaired biorheology and increased adhesion-mediated vaso-occlusion, (c) hemolysis-mediated endothelial dysfunction, and (d) concerted activation of sterile inflammation (Toll-like receptor 4- and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD. This review provi...

Source: Annual Review of Pathology - October 17, 2018 Category: Pathology Authors: Sundd P, Gladwin MT, Novelli EM Tags: Annu Rev Pathol Source Type: research