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Overview

Sickle cell disease (SCD) is an autosomal recessive disease caused by a single point mutation in the gene encoding the β-globin chain of hemoglobin.1 The most common form of SCD is caused by the inheritance of homozygous mutant hemoglobin S (HbSS; occurring in up to 75% of patients), whereas approximately 25% of patients have compound heterozygosity of hemoglobin S with another β-globin chain variant (ie, hemoglobin C, D-Punjab, O-Arab, and E).1-4 The mutant sickle cell hemoglobin polymerizes within the erythrocyte during deoxygenation, altering erythrocyte rheology and causing microvascular obstruction and hemolytic anemia.1-4 As described in early chapters on mechanisms of disease and summarized in Figure 14-1, the pathogenesis is determined upstream by the extent of hemoglobin S polymerization, which leads to the following 2 major downstream pathologic events: microvascular occlusion (vaso-occlusion) with ischemia-reperfusion tissue injury and infarction,5,6 and hemolytic anemia, which releases cell free hemoglobin and other erythrocytic products, such as adenosine diphosphate (ADP) and arginase 1, from the red blood cells, reducing nitric oxide (NO) signaling and generating reactive oxygen species.7-11 These pathobiologic processes may act in concert to activate inflammatory pathways involving selectin-mediated adhesion and inflammasome-mediated sterile inflammation.4 For example, oxidation of hemoglobin leads to heme release and downstream activation of P-selectin–dependent platelet-neutrophil interactions and toll-like receptor 4 (TLR4)-dependent and -independent sterile inflammation signaling pathways.12-15 Cycles of ischemia-reperfusion tissue injury and infarction likely also release damage-associated molecular proteins (DAMPs), such as mitochondrial DNA, that can also activate toll-like receptor and NLRP (Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing), also abbreviated as NALP (NACHT, LRR, and PYD domains–containing protein) inflammasome-dependent sterile inflammation. Furthermore, steady-state intravascular hemolysis releases erythrocyte DAMPs (eDAMPs) that may activate the innate immune system, priming it for a second hit, such as infection or trauma, that activates severe inflammation and vaso-occlusive events.4,16 During acute episodes of pain crisis, the intensity of both vaso-occlusion and hemolytic anemia may increase dramatically, leading to severe acute organ injury and severe pain, sometimes culminating in acute lung injury (called the acute chest syndrome), cor pulmonale, multiorgan dysfunction and failure, and death.2,4 See Figure 14-1 for an overview of the major pathophysiologic mechanisms that drive SCD.

FIGURE 14-1

Molecular pathophysiology of sickle cell disease. A. HbS polymerization. B. Vaso-occlusion. C. Hemolytic anemia and endothelial dysfunction. D. Sterile inflammation and inflammasome activation. Hb, hemoglobin; IL, interleukin; NETs, neutrophil extracellular traps; ROS, reactive oxygen species; XO, xanthine oxidase. Other abbreviations are defined in the text. Modified from Sundd P, Gladwin MT, Novelli EM. Pathophysiology of Sickle Cell Disease. Annu Rev Pathol. 2019;14:263-292.

In the current era, the epidemiology of SCD can be characterized by 2 divergent outcomes, one good and the other quite ominous. The first involves dramatic improvement in outcomes for children with SCD, with rapid improvement ...

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