Sickle Cell Anemia · Hb SS

Description

Sickle cell anemia is the homozygous form of sickle cell disease. Two copies of the HbS variant in HBB, the gene that encodes the beta-globin subunit of hemoglobin, produce hemoglobin that polymerizes when deoxygenated. Red cells deform into a sickle shape, lose flexibility, and occlude small vessels. The clinical course includes chronic hemolytic anemia, recurrent vaso-occlusive crises, acute chest syndrome, splenic infarction in early childhood, stroke risk, progressive kidney disease, retinopathy, and cumulative organ damage. Inheritance is autosomal recessive. The causative variant is a single nucleotide change at HBB codon 6 producing a glutamic acid to valine substitution.

HbSS is the most common severe hemoglobinopathy worldwide. In the United States, sickle cell disease affects approximately 1 in 365 Black or African American newborns. Detection is by newborn screening on the dried blood spot using isoelectric focusing or high-performance liquid chromatography, with a confirmatory second method and HBB sequencing where the screening pattern is ambiguous. All US states screen every newborn for sickle cell disease, and most birth countries in sub-Saharan Africa do not.

Children with HbSS receive penicillin prophylaxis from infancy through age 5 to reduce pneumococcal sepsis risk, transcranial Doppler screening from age 2 to age 16 to identify children at high stroke risk, and routine immunizations against encapsulated organisms.

Treatments to date

Hydroxyurea is the foundation of disease-modifying therapy. It raises fetal hemoglobin, reduces HbS polymerization, and lowers crisis frequency. Droxia, the adult formulation, was approved by the FDA in March 1998. Siklos, the pediatric formulation, was approved in December 2017 for children ages 2 and older.

L-glutamine oral powder, marketed as Endari, was approved by the FDA in July 2017 for sickle cell disease ages 5 and older to reduce acute complications. Crizanlizumab, a P-selectin inhibitor marketed as Adakveo, was approved by the FDA in November 2019 to reduce vaso-occlusive crisis frequency in patients 16 and older. Voxelotor, a hemoglobin oxygen-affinity modulator marketed as Oxbryta, was approved by the FDA in November 2019. Pfizer voluntarily withdrew Oxbryta from worldwide markets in September 2024 after post-marketing data raised concerns about excess vaso-occlusive crises and deaths.

Two gene therapies were approved by the FDA on the same day in December 2023 for sickle cell disease in patients 12 and older with a history of recurrent vaso-occlusive crises. Casgevy, exagamglogene autotemcel, is a CRISPR-Cas9 edit of the BCL11A erythroid enhancer that reactivates fetal hemoglobin production. Lyfgenia, lovotibeglogene autotemcel, is a lentiviral gene addition therapy that introduces an anti-sickling beta-globin gene. Both require myeloablative conditioning and autologous hematopoietic stem cell collection. List prices are 2.2 million dollars for Casgevy and 3.1 million dollars for Lyfgenia.

Allogeneic hematopoietic stem cell transplant from a matched sibling donor remains a curative option, used most commonly in pediatric centers for children with severe disease and an available donor. Chronic transfusion programs are standard for primary and secondary stroke prevention. Supportive care covers acute pain crises, transfusion for acute chest syndrome, hydroxyurea optimization, and surveillance for end-organ complications.