Pathophysiology of Sickle Cell Disease

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 end-organ 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 provides an exhaustive overview of the current understanding of the molecular pathophysiology of SCD, how this pathophysiology contributes to complications of the central nervous and cardiopulmonary systems, and how this knowledge is being harnessed to develop current and potential therapies.

Keywords: hemolysis; infarction; inflammation; oxidative stress; reperfusion injury; sickle cell anemia.

Figure 1

Molecular pathophysiology of sickle cell disease. (a) A single-nucleotide polymorphism in the β-globin gene leads to substitution of valine for glutamic acid at the sixth position in the β-globin chain. Following deoxygenation, the mutated hemoglobin (HbS) molecules polymerize to form bundles. The polymer bundles result in erythrocyte sickling (clockwise), which in turn results in (b) impaired rheology of the blood and aggregation of sickle erythrocytes with neutrophils, platelets, and endothelial cells to promote stasis of blood flow, referred to as vaso-occlusion. Vaso-occlusion promotes ischemia-reperfusion (I-R) injury (clockwise). (a) Hemoglobin (Hb) polymer bundles also promote hemolysis or lysis of erythrocytes (counterclockwise), which (c) releases cell-free Hb into the blood circulation. Oxygenated Hb (Fe²⁺) promotes endothelial dysfunction by depleting endothelial nitric oxide (NO) reserves to form nitrate (NO₃⁻) and methemoglobin (Fe3⁺). Alternatively, Hb can also react with H₂O₂ through the Fenton reaction to form hydroxyl free radical (OH^•) and methemoglobin (Fe³⁺). Also, NADPH oxidase, xanthine oxidase (XO), and uncoupled endothelial NO synthase (eNOS) generate oxygen free radicals to promote endothelial dysfunction. Methemoglobin (Fe³⁺) degrades to release cell-free heme (counterclockwise), which is a major erythrocyte damage-associated molecular pattern (DAMP). (d) Reactive oxygen species (ROS) generation, Toll-like receptor 4 (TLR4) activation, neutrophil extracellular trap (NET) generation, release of tissue or cell-derived DAMPs, DNA, and other unknown factors (?) triggered by cell-free heme or I-R injury can contribute to sterile inflammation by activating the inflammasome pathway in vascular and inflammatory cells to release IL-1β. Finally, sterile inflammation further promotes vaso-occlusion through a feedback loop by promoting adhesiveness of neutrophils, platelets, and endothelial cells.

Figure 2

Current and future therapies targeting molecular pathobiology of sickle cell disease. (a) Drugs capable of modulating hemoglobin (Hb) polymerization, erythrocyte dehydration, and Hb oxygen affinity. (b) Drugs capable of preventing vaso-occlusion by inhibiting adhesive interactions between leukocytes, platelets, or endothelial cells and erythrocytes. (c) Drugs capable of preventing endothelial dysfunction by scavenging Hb and reactive oxygen species (ROS) or promoting nitric oxide (NO) synthesis. (d) Drugs capable of preventing sterile inflammation by scavenging heme and ROS, digesting neutrophil extracellular traps (NETs), inhibiting Toll-like receptor 4 (TLR4) or inflammasome activation, and inhibiting IL-1β-dependent innate immune signaling. Drugs approved by the US Food and Drug Administration (hydroxyurea and l-glutamine) are shown in bold font.

Figure 3

Endothelial dysfunction in sickle cell disease. Anemia and intravascular hemolysis lead to pulmonary vascular disease and diastolic heart dysfunction, both of which contribute to morbidity (reduced exercise capacity) and death (75). Figure adapted with permission from Reference . Abbreviations: eDAMP, erythrocyte damage-associated molecular pattern; PA, pulmonary artery; PVR, pulmonary vascular resistance; RA, right atrium; RV, right ventricle.

Figure 4

Mechanisms leading to the development of acute lung injury (ALI) and acute chest syndrome (ACS). Microbial pathogens interact with alveolar epithelial and inflammatory cells to promote release of proinflammatory cytokines. Heme and cell-free hemoglobin released from lysed sickle erythrocytes function as erythrocyte damage-associated molecular patterns (eDAMPs) to trigger Toll-like receptor 4 and inflammasome signaling in vascular and inflammatory cells. P-selectin-dependent platelet–neutrophil aggregates promote vaso-occlusion and microthrombosis in lung arterioles, leading to loss of pulmonary blood flow. Fat and marrow emboli released from necrotic bones obstruct the microcirculation and stimulate further inflammation by activating phospholipase A and other enzymes. Lung vaso-occlusion promotes ischemia-reperfusion injury, failure of the blood–air barrier, infarction, alveolar flooding, neutrophil recruitment, degranulation, release of neutrophil extracellular traps (NETosis), and oxidative burst, leading to epithelial injury, formation of hyaline membranes, and respiratory failure, all of which are hallmarks of ALI and ACS.