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Sickle Cell DiseaseA Review

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Abstract

Importance  Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation of long chains of hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 300 000 infants are born annually worldwide with SCD. Most individuals with SCD live in sub-Saharan Africa, India, the Mediterranean, and Middle East; approximately 100 000 individuals with SCD live in the US.

Observations  SCD is diagnosed through newborn screening programs, where available, or when patients present with unexplained severe atraumatic pain or normocytic anemia. In SCD, sickling and hemolysis of red blood cells result in vaso-occlusion with associated ischemia. SCD is characterized by repeated episodes of severe acute pain and acute chest syndrome, and by other complications including stroke, chronic pain, nephropathy, retinopathy, avascular necrosis, priapism, and leg ulcers. In the US, nearly all children with SCD survive to adulthood, but average life expectancy remains 20 years less than the general population, with higher mortality as individuals transition from pediatric to adult-focused health care systems. Until 2017, hydroxyurea, which increases fetal hemoglobin and reduces red blood cell sickling, was the only disease-modifying therapy available for SCD and remains first-line therapy for most individuals with SCD. Three additional therapies, L-glutamine, crizanlizumab, and voxelotor, have been approved as adjunctive or second-line agents. In clinical trials, L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo. Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo. Voxelotor increased hemoglobin by at least 1 g/dL, significantly more than placebo (51% vs 7%). Hematopoietic stem cell transplant is the only curative therapy, but it is limited by donor availability, with best results seen in children with a matched sibling donor. While SCD is characterized by acute and chronic pain, patients are not more likely to develop addiction to pain medications than the general population.

Conclusions and Relevance  In the US, approximately 100 000 people have SCD, which is characterized by hemolytic anemia, acute and chronic pain, acute chest syndrome; increased incidence of stroke, nephropathy, and retinopathy; and a life span that is 20 years shorter than the general population. While hydroxyurea is first-line therapy for SCD, L-glutamine, crizanlizumab, and voxelotor have been approved in the US since 2017 as adjunctive or second-line treatments, and hematopoietic stem cell transplant with a matched sibling donor is now standard care for severe disease.

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Article Information

Corresponding Author: Patricia Kavanagh, MD, Boston University School of Medicine/Boston Medical Center, 801 Albany St, Second Floor, Boston, MA 02119 (patricia.kavanagh@bmc.org).

Accepted for Publication: May 31, 2022.

Author Contributions: Dr Kavanagh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kavanagh.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Fasipe.

Supervision: Kavanagh.

Conflict of Interest Disclosures: Dr Kavanagh reported being a salaried employee of EBSCO (working as part of the team that creates its clinical point-of-care tool DynaMed) and serving as senior deputy editor of Systematic Literature Surveillance. Dr Fasipe reported grants from Pfizer; personal fees from Novartis, Forma Therapeutics, Global Blood Therapeutics, Emmaus, and bluebird bio (consultancies) outside the submitted work; and for nonprofit foundations, serving on the Quality Measure Oversight Committee for the American Society of Hematology, the Technical Expert Panel for Sickle Cell Disease Quality Measures (chair), and the Hemoglobinopathy Special Interest Group for the American Society of Pediatric Hematology/Oncology (chair). Dr Wun reported personal fees from Pfizer, Inc (steering committee) and from Glycomimetics, Inc and Global Blood Therapeutics, Inc (advisory boards) outside the submitted work; and serving on the American Society of Hematology Sickle Cell Disease Research Collaborative Steering Committee and the American Society of Hematology Sickle Cell Disease Guideline Committee (a nonprofit professional organization).

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