Sickle cell disease (SCD) is a genetic blood disorder where red blood cells become rigid, sticky, and shaped like crescent moons or sickles instead of their normal flexible disc shape. It affects about 100,000 people in the United States and millions worldwide, and those with the disease have an estimated life expectancy more than 20 years shorter than average.
What Happens Inside the Blood
Normal red blood cells contain a protein called hemoglobin that carries oxygen throughout the body. In sickle cell disease, a single change in the gene that builds hemoglobin swaps one amino acid for another, producing an abnormal version called hemoglobin S. This tiny difference has enormous consequences.
When hemoglobin S releases its oxygen in tissues that need it, the protein molecules stick to each other and form long, stiff fibers inside the red blood cell. These fibers stretch the cell into its characteristic sickle shape and make it rigid. Normal red blood cells are soft and flexible enough to squeeze through the smallest blood vessels. Sickled cells cannot do this easily. They get stuck, block blood flow, and die much sooner than healthy red blood cells, which leads to chronic anemia. A normal red blood cell lives about 120 days. A sickled cell may last only 10 to 20 days.
How Sickle Cell Is Inherited
Sickle cell disease is inherited in an autosomal recessive pattern, meaning a child must receive the abnormal gene from both parents to develop the disease. A person who inherits just one copy is said to have sickle cell trait. They typically don’t have symptoms but can pass the gene to their children.
If both parents carry sickle cell trait, each pregnancy carries a 25% chance the child will have sickle cell disease, a 50% chance the child will have sickle cell trait, and a 25% chance the child will inherit neither.
Types of Sickle Cell Disease
Not all sickle cell disease is the same. The most common and severe form, called HbSS or sickle cell anemia, occurs when a person inherits two copies of the hemoglobin S gene. These individuals tend to experience more frequent pain crises, hospital admissions, strokes, acute chest syndrome, and infections.
A milder form called HbSC disease occurs when someone inherits one hemoglobin S gene and one hemoglobin C gene (a different hemoglobin mutation). People with HbSC disease generally have less severe anemia and fewer hospitalizations, though they are more prone to eye complications, particularly damage to the retina. Pain crises remain the leading cause of hospitalization in both types. Other forms exist as well, including combinations with beta-thalassemia, another hemoglobin disorder.
Pain Crises and What Triggers Them
The hallmark symptom of sickle cell disease is the vaso-occlusive crisis, commonly called a pain crisis. This happens when sickled red blood cells stick to the walls of blood vessels and to each other, blocking blood flow to tissues. The process is not just mechanical clogging. It involves a cascade of inflammation: sickled cells trigger the vessel lining to produce inflammatory signals, which attract white blood cells that further narrow the vessel.
Pain crises can be triggered by emotional stress, physical exertion, dehydration, cold temperatures, and infections. Stress and exertion increase adrenaline-like hormones that make sickled cells stickier to vessel walls. Episodes of rapid red blood cell destruction can also overwhelm the body’s ability to compensate and set off a crisis. The pain can strike anywhere but commonly affects the chest, abdomen, joints, and bones. Episodes may last hours to days and often require hospital-level pain management.
Long-Term Organ Damage
Over years, the repeated cycles of blood vessel blockage and oxygen deprivation take a toll on organs throughout the body. The spleen is often the first organ affected. In children with sickle cell disease, sickled cells can become trapped in the spleen, causing it to swell dangerously in what’s called splenic sequestration. Over time, repeated damage leaves the spleen nonfunctional, which increases vulnerability to certain bacterial infections.
Kidney disease develops in about 25% of older adults with sickle cell disease and accounts for roughly half of deaths in that age group. The kidneys are especially vulnerable because they naturally have areas of low oxygen, which promotes sickling. Lung complications, including a form of high blood pressure in the lung’s arteries, are another major cause of decline. Brain damage from silent or overt strokes can begin in childhood. Pulmonary and kidney failure are the leading complications in hospitalized patients over age 50.
How Sickle Cell Is Diagnosed
In the United States, every newborn is screened for sickle cell disease as part of routine newborn testing. A few drops of blood from the baby’s heel are analyzed to identify abnormal hemoglobin types. If the initial screen is positive, genetic testing can confirm whether the child has sickle cell disease or sickle cell trait.
Prenatal testing is also available as early as 8 to 10 weeks into pregnancy. This testing uses a sample of amniotic fluid or tissue from the placenta to look for the sickle cell gene directly. For adults who were never tested, a blood test can determine whether the body produces hemoglobin S and how much.
Treatments That Reduce Symptoms
The most widely used medication is hydroxyurea, which can be prescribed to children as young as 9 months. It works by boosting the body’s production of fetal hemoglobin, a type of hemoglobin that everyone makes before birth but normally stops producing. Fetal hemoglobin interferes with the clumping of hemoglobin S, so red blood cells sickle less often. This reduces pain crises and other serious complications.
Another medication, crizanlizumab, is given through a monthly IV infusion. It works by preventing blood cells from sticking to vessel walls, which helps reduce pain crises, lowers the need for transfusions, and dampens inflammation. Regular blood transfusions are also used for some patients, particularly those at high risk for stroke.
Gene Therapy: A Potential Cure
In December 2023, the FDA approved two gene therapies for sickle cell disease, both available to patients 12 and older who experience recurrent pain crises. These are the first gene therapies ever approved for the condition.
Casgevy uses CRISPR gene-editing technology, a tool that can precisely cut and modify DNA. A patient’s own blood stem cells are removed, edited in a lab to boost fetal hemoglobin production, and then transplanted back. The increased fetal hemoglobin prevents red blood cells from sickling. This was the first FDA-approved therapy to use CRISPR technology for any disease.
Lyfgenia takes a different approach. It uses a virus-based delivery system to insert a modified gene into the patient’s stem cells. This gene produces a therapy-derived hemoglobin that functions like normal adult hemoglobin, reducing the risk of sickling and blood vessel blockage. Both therapies require intensive preparation, including chemotherapy to clear existing bone marrow before the modified cells are transplanted back, and a lengthy recovery period.
Living With Sickle Cell Disease
Daily life with sickle cell disease centers on preventing crises and managing chronic symptoms. Staying well-hydrated, avoiding temperature extremes, managing stress, and keeping up with vaccinations (especially important given the spleen’s compromised function) all help reduce the frequency of complications. Children with the disease need regular screening for stroke risk, often with specialized ultrasound of blood vessels in the brain.
Chronic pain, fatigue from anemia, and the unpredictability of crises affect quality of life significantly. Many adults with sickle cell disease also face gaps in care during the transition from pediatric to adult medicine, and access to specialists varies widely. The disease disproportionately affects people of African, Mediterranean, Middle Eastern, and South Asian descent, populations that have historically faced disparities in healthcare access and research funding.