Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

Abstract

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

Keywords: crizanlizumab; fetal hemoglobin; hydroxyurea; l-glutamine; sickle cell disease; vaso-occlusive crisis; voxelotor.

Figure 1.

Contribution of intravascular hemolysis to vasculopathy and vaso-occlusion. Intravascular hemolysis produces free hemoglobin, which drives Fenton reactions to produce oxidants and scavenges NO by a deoxygenation reaction. Intravascular hemolysis also releases red cell arginase 1 into plasma, where it can deplete plasma l-Arg, the required substrate for NO production by eNOS. Oxidized hemoglobin releases free heme, which can activate the release of PIGF and ET-1. These combined pathways contribute to chronic vasculopathy, platelet activation, and pulmonary hypertension. Heme also primes the innate immune system to acute rises in endogenous (HMGB1) and exogenous (LPS) ligands of TLR4. These, in turn, activate production of ROS, NETs, and downstream activation of the inflammasome, producing inflammatory cytokines and other mediators that promote expression of adhesion receptors and ligands on endothelium and blood cells. Intravascular hemolysis also releases adenine nucleotides, including ATP and ADP, which further contributes to platelet activation. There is also some evidence that adenosine binds receptors on red cells, resulting in increased 2,3-diphosphoglycerate and sphingosine-1-phosphate, associated with lower oxygen affinity of hemoglobin (not shown). Proteins on the surface of the activated endothelium (P-selectin, E-selectin, VCAM-1, ICAM-1) interact with adhesive platelets, neutrophils, and sickle erythrocytes, producing vaso-occlusion and acute chest syndrome. Intravascular hemolysis also releases asymmetric dimethylarginine, which inhibits eNOS. CRP, C-reactive protein; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; HMGB1, High mobility group box 1; l-Arg, l-arginine; LPS, lipopolysaccharide; NET, neutrophil extracellular trap; NO, nitric oxide; Orn, ornithine; PLGF, placenta growth factor; ROS, reactive oxygen species; SAA, serum amyloid A. From Kato et al. with permission from the American Society for Clinical Investigation.

Figure 2.

Sickle cell pain crises: role of pharmaceutical interventions in sequential pathogenic mechanisms, including adhesion, oxidative stress, inflammation, hemolysis, and HbF induction. HbF, fetal hemoglobin; IFNγ, interferon gamma; IL-4, interleukin 4; iNKT, invariant natural killer T; TNFα, tumor necrosis factor alpha. From Field, with permission from the American Society of Hematology.