Disease Overview

Sickle cell disease is the most common genetic disease in the United States.  It is an autosomal recessive disease that is characterized by sickle-shaped red blood cells in patients with anemia. Normal adult hemoglobin is a soluble tetramer consisting of 2 alpha chains and 2 beta chains. In sickle cell disease, a point mutation in the beta chain causes the sickling of erythrocytes, resulting in abnormal hemoglobin. The sickle-shaped red blood cells can clog small blood vessels, producing local hypoxia and possible obstruction of blood vessels. Sickle cell disease can reduce life expectancy and quality of life if left untreated. This disease predominantly affects African Americans at a rate of 1 in 500. One in 12 African Americans carry the recessive gene mutation, and approximately 300,000 infants are born with the disease each year. 

Classification

Sickle cell disease is an umbrella term that encompasses a set of disorders characterized by at least 1 HbS allele. The most common mutation is a substitution of valine for glutamic acid at position 6 on chromosome 11 (HbS). As a result, the hemoglobin chain becomes more hydrophobic, leading to a precipitation of the molecule and sickling of erythrocytes. In heterozygous patients (HbS/A), 1 of the 2 beta chains are affected which causes most patients to be asymptomatic. Homozygous patients (HbS/S) inherit 2 abnormal HbS genes which causes patients to be symptomatic. Other disorders include sickle-hemoglobin C disease (HbS/C), sickle β-thalassemia, and sickle hemoglobin D,O, and E disease (HbS/D, HbS/E, and HbS/O). 

Signs and Symptoms

Symptoms of sickle cell disease (SCD) manifest early in life, often appearing as early as 6 months of age. Complications arise primarily from vaso-occlusion and encompass conditions such as vaso-occlusive crisis (severe pain episodes), acute chest syndrome, susceptibility to infections by encapsulated organisms (due to autosplenectomy), cerebrovascular events, splenic sequestration, priapism, and aplastic crisis.

Diagnosis

Sickle cell disease (SCD) is diagnosed using a test called hemoglobin electrophoresis. In the United States, newborn screening is commonly used to detect SCD early.

Disease Management and Treatment

Treatment for SCD falls into three main categories: maintaining overall health, managing complications, and potentially curing the disease. Health maintenance includes educating patients, medications to improve anemia, vaccinations, and penicillin to prevent infections. Complications like acute chest syndrome and vaso-occlusive crises (severe pain episodes) are typically treated with pain relievers, fluids, and supportive care, although specific treatments vary based on the complication. Patients with SCD may receive blood transfusions to improve blood flow, increase oxygen-carrying capacity of the blood, and prevent further complications. This is because blood transfusions are able to replace abnormal red blood cells with normal cells. Chronic blood transfusions are performed to reduce long-term complications such as stroke for patients with SCD. Patients with SCD can be cured with hematopoietic stem cell transplant (HSCT). This transplant has the ability to prevent vaso-occlusive events, acute chest syndrome, stroke, and progression of cerebrovascular disease. Without this procedure, individuals with SCD often have a shorter lifespan, living 20 to 30 years less than average. Treatments available for patients with SCD are Hydroxyurea, Endari, Adakveo, and Oxbyrta. Hydroxyurea is the standard treatment for SCD. It increases the level of fetal hemoglobin and decreases hemoglobin S polymerization. Endari (L-glutamine) is a medication used for patients with SCD who are at least 5 years old. This medication is used to reduce complications associated with SCD by reducing oxidative stress. Adakveo (crizanlizumab-tmca) is a monoclonal antibody recommended for patients aged 16 years and older. This therapy prevents vaso-occlusive events by binding to P-selectin and disrupting interactions among endothelial cells, platelets, leukocytes, and red blood cells. Oxbyrta (voxelotor) is indicated for patients 12 years and older and used as an alternative therapy for patients who do not respond well to hydroxyurea. It increases the binding affinity of hemoglobin to oxygen, ultimately inhibiting HbS polymerization and stabilizing red blood cells. Gene therapy such as Casgevy and Lyfgenia are other treatment options for patients with SCD. Casgevy™ (exagamglogene autotemcel [exa-cel]) is a CRISPR/Cas9 genome-edited cell-based therapy indicated for patients aged 12 years and older with recurrent vaso-occlusive crises. Lyfgenia™ (lovotibeglogene autotemcel [lovo-cel]), is a one-time ex-vivo lentiviral vector gene therapy indicated for patients aged 12 years and older with a history of vaso-occlusive events.