Sickle cells are red blood cells that have become stiff and curved into a crescent or sickle shape, instead of the flexible, round disc shape of normal red blood cells. This happens because of an inherited change in hemoglobin, the protein inside red blood cells that carries oxygen. When hemoglobin is altered in a specific way, it can clump into rigid fibers that distort the cell’s shape, causing it to get stuck in small blood vessels and block blood flow. This is the core problem behind sickle cell disease, a condition affecting an estimated 7.74 million people worldwide.
What Makes Red Blood Cells Sickle
Normal red blood cells are soft and flexible, allowing them to squeeze through the tiniest blood vessels in your body. In sickle cell disease, a single change in the gene that builds part of the hemoglobin molecule swaps out one amino acid for another on the protein’s surface. Specifically, a negatively charged building block (glutamic acid) is replaced by a water-repelling one (valine). That one substitution changes everything.
When this altered hemoglobin, called hemoglobin S, releases its oxygen in the tissues, the molecules stick together and form long, rigid fibers inside the red blood cell. These fibers stretch the cell into its characteristic crescent shape and make it far less flexible. The first fiber that forms acts as a seed: new fibers quickly sprout off its surface, rapidly filling the cell. Once sickled, these cells can jam together in small blood vessels, cutting off oxygen to surrounding tissue and triggering intense pain.
How Sickle Cell Disease Is Inherited
Sickle cell disease follows an autosomal recessive inheritance pattern, meaning a child must inherit two copies of an altered hemoglobin gene to develop the disease. One copy comes from each parent. Parents who carry a single copy are called carriers and typically have no symptoms themselves.
The most common form, sometimes called HbSS disease, occurs when a person inherits two copies of the hemoglobin S gene. Other forms of sickle cell disease happen when someone inherits one hemoglobin S gene and a second gene for a different abnormal hemoglobin. Without a gene to produce normal adult hemoglobin, red blood cells break down quickly, leading to chronic anemia and the complications that define the disease.
Sickle Cell Trait vs. Sickle Cell Disease
People who inherit just one copy of the sickle cell gene have what’s known as sickle cell trait. This is not the same as having sickle cell disease, and it does not turn into sickle cell disease over time. Most people with sickle cell trait never experience serious medical problems.
In rare cases, though, the trait can cause symptoms when the body is under extra stress for oxygen. This includes intense physical activity, being at high altitude (like mountain climbing or flying in an unpressurized aircraft), dehydration, or exposure to extreme temperatures. Some people with sickle cell trait also experience kidney or spleen damage over time.
Pain Crises and Other Symptoms
The hallmark of sickle cell disease is the vaso-occlusive crisis, commonly called a pain crisis. Sickled cells traveling through small blood vessels get stuck and block blood flow, starving tissues of oxygen. The pain can strike suddenly, range from mild to severe, and last anywhere from hours to days or longer. It most commonly hits the hands, feet, chest, and back, though it can occur anywhere in the body.
Beyond pain episodes, sickle cell disease causes chronic anemia because sickled red blood cells break apart much faster than normal ones. This ongoing shortage of red blood cells leads to fatigue, weakness, and pale skin.
Long-Term Effects on the Body
Over years, repeated blockages and oxygen deprivation take a toll on major organs.
- Spleen: Sickled cells can get trapped in the spleen, causing it to enlarge rapidly. This trapping, called splenic sequestration, pulls red blood cells out of circulation and can cause dangerously severe anemia. A damaged spleen also weakens the body’s defense against certain bacterial infections.
- Kidneys: Sickle cell disease makes it harder for the kidneys to concentrate urine, often leading to frequent urination and bedwetting in children. Over time, scarring in the kidney’s filters can progress to kidney failure.
- Lungs: Sickling in the blood vessels of the lungs can cause acute chest syndrome, a medical emergency involving chest pain, fever, and difficulty breathing. It deprives lung tissue of oxygen and can cause lasting damage.
Estimated life expectancy for people with sickle cell disease in the United States is more than 20 years shorter than the general population’s average. When quality of life is factored in, that gap widens to more than 30 years.
Who Is Most Affected
Sickle cell disease is most common among people of African, Mediterranean, Middle Eastern, and Indian descent. Sub-Saharan Africa accounts for nearly 80% of global cases. In 2021 alone, an estimated 515,000 babies were born with the disease worldwide, according to the World Health Organization.
The gene persists in these populations because carrying a single copy (sickle cell trait) provides some protection against malaria, a major survival advantage in regions where the parasite is widespread.
How It’s Diagnosed
In the United States and many other countries, sickle cell disease is detected through newborn screening. A few drops of blood are collected from a heel prick shortly after birth and analyzed for abnormal hemoglobin. The disease can also be diagnosed before birth, as early as 8 to 10 weeks into pregnancy, using a sample of amniotic fluid or tissue from the placenta.
If screening results are unclear, genetic testing can confirm whether someone carries one or two copies of the sickle cell gene. Blood tests identify the presence and amount of hemoglobin S, while genetic tests look directly at the gene itself.
Treatment and Gene Therapy
For decades, managing sickle cell disease meant treating symptoms: pain medication during crises, blood transfusions for severe anemia, and daily medications that boost production of a form of hemoglobin normally found in newborns (fetal hemoglobin), which prevents sickling.
In December 2023, the FDA approved two gene therapies that represent a fundamentally different approach. Both are approved for patients 12 and older with a history of pain crises. In each treatment, a patient’s own blood stem cells are removed, genetically modified in a lab, and then transplanted back into the body.
One therapy, Casgevy, uses CRISPR gene-editing technology to reprogram stem cells so they produce high levels of fetal hemoglobin, which blocks red blood cells from sickling. It was the first CRISPR-based therapy ever approved by the FDA. The other, Lyfgenia, uses a different technique to insert a gene that produces a hemoglobin very similar to the normal adult version, giving red blood cells a lower risk of sickling and blocking blood flow. Both therapies aim to address the root cause of the disease rather than just managing its symptoms.