Sickle cell disease affects nearly every organ system in the body. What begins as a single mutation in hemoglobin, the oxygen-carrying protein in red blood cells, cascades into damage across the circulatory, pulmonary, renal, neurological, musculoskeletal, immune, and visual systems. Understanding how each system is involved helps explain why sickle cell disease causes such a wide range of symptoms and complications over a person’s lifetime.
How the Disease Starts in the Blood
The root of sickle cell disease is an abnormal form of hemoglobin called hemoglobin S. When hemoglobin S releases its oxygen, the molecules stick together and form long, stiff fibers inside red blood cells. This process, called polymerization, physically warps the normally flexible, disc-shaped cells into rigid crescents or “sickles.” Once a single fiber forms, new fibers rapidly branch off its surface, creating a dense mesh that stretches the cell membrane. These misshapen cells can’t squeeze through small blood vessels the way healthy cells do, and they break apart far more easily, typically surviving only 10 to 20 days instead of the normal 120.
This combination of blockages and premature cell destruction is what drives damage throughout the body. Blocked vessels starve tissues of oxygen, while the constant breakdown of red blood cells releases free hemoglobin into the bloodstream, triggering inflammation and depleting nitric oxide, a molecule that normally keeps blood vessels relaxed and open.
Blood Vessels and the Cardiovascular System
Sickle cells don’t just passively get stuck in narrow vessels. They actively adhere to the walls of blood vessels through sticky surface proteins, and they recruit white blood cells and platelets into the process. White blood cells that attach to the vessel wall can even capture passing sickle cells, building up a plug that blocks blood flow entirely. This chain reaction is what causes vaso-occlusive crises, the episodes of intense pain that are the hallmark of the disease.
Over time, the constant damage to vessel linings creates chronic inflammation. The inner surface of blood vessels stays in a persistently activated state, producing more adhesion molecules and reactive oxygen species that further injure surrounding tissue. This ongoing vascular injury contributes to one of the most serious cardiovascular complications: pulmonary hypertension, or high blood pressure in the arteries of the lungs. Pulmonary hypertension develops in 6 to 11% of people with sickle cell disease and significantly raises the risk of early death. Elevated pressure in the lung arteries increases the risk of death roughly fivefold, and at higher levels, that risk increases tenfold.
The Lungs
Acute chest syndrome is the leading cause of death among people with sickle cell disease, responsible for about 25% of all deaths. It involves a new area of lung inflammation visible on imaging, combined with symptoms like chest pain, fever above 38.5°C (101.3°F), difficulty breathing, wheezing, or a drop in oxygen levels. The mortality rate per episode is about 1.1% in children but climbs to as high as 9% in adults.
Acute chest syndrome can be triggered by a lung infection, fat released from bone marrow during a pain crisis, or sickling within the lung’s own blood vessels. Repeated episodes cause scarring and progressive loss of lung function, which in turn raises the risk of developing pulmonary hypertension. Even between acute episodes, many people with sickle cell disease have lower baseline oxygen levels and reduced lung capacity compared to the general population.
The Kidneys
The kidneys are especially vulnerable because of their unusual blood supply. The inner part of the kidney, called the medulla, naturally has low oxygen levels, high salt concentration, and acidic conditions, all of which promote hemoglobin S polymerization. Damage often begins in childhood without any obvious symptoms.
The earliest detectable sign is usually excess protein leaking into the urine, a condition called albuminuria. In children under 10, roughly 27% already show signs of early kidney damage. The prevalence of albuminuria rises steadily with age: about 28% of patients aged 16 to 25, 38% of those aged 26 to 35, and 50% of those aged 36 to 45. Over time, the kidneys’ filtering capacity declines. One study found that after five years of follow-up, nearly 42% of patients had progressed to chronic kidney disease. About 4% develop nephrotic syndrome, a severe form of protein loss that signals poor long-term kidney survival.
The Brain and Nervous System
Sickle cell disease carries a strikingly high stroke risk, particularly in children. Without screening or preventive treatment, about 10% of children with sickle cell anemia will have a stroke, and these events can begin in infancy. Strokes in children with sickle cell disease tend to affect large arteries in the brain, causing significant disability.
Annual screening with transcranial Doppler ultrasound, which measures blood flow velocity in the brain’s major arteries, can identify children at high risk before a stroke occurs. Children with abnormally high flow velocities can then receive regular blood transfusions, which dramatically reduce stroke risk. Despite strong guidelines recommending annual screening, only about 40% of eligible children actually receive it. Beyond overt strokes, many children and adults develop “silent” brain infarcts, small areas of damage that don’t cause obvious symptoms but can impair memory, attention, and academic performance over time.
The Immune System and Spleen
The spleen normally filters bacteria from the bloodstream, particularly encapsulated organisms like pneumococcus. In sickle cell disease, repeated sickling within the spleen’s tiny blood vessels causes progressive scarring and loss of function. This process begins remarkably early: splenic dysfunction has been documented in infants as young as 3 to 6 months, and 87% of infants with the most severe form of sickle cell disease show impaired splenic function by an average age of about 13 months.
By later childhood, most people with sickle cell anemia have a spleen that is essentially nonfunctional, a condition called autosplenectomy. This leaves them highly susceptible to life-threatening bacterial infections, which is why children with sickle cell disease take daily preventive antibiotics starting in infancy and receive additional vaccinations against encapsulated bacteria. Before these preventive measures became standard, overwhelming infection was a leading cause of death in young children with the disease.
Bones and Joints
Bone pain is one of the most frequent reasons people with sickle cell disease seek emergency care. Vaso-occlusive episodes can affect any bone, but they most commonly involve the long bones of the arms and legs, the spine, and the pelvis. In young children, painful swelling of the hands and feet, called dactylitis, is often the first symptom of the disease.
The most serious long-term skeletal complication is avascular necrosis, in which blocked blood supply causes bone tissue to die. The hip is the most commonly affected joint. Up to 50% of people with sickle cell disease develop avascular necrosis by age 35, and many eventually require joint replacement surgery. The shoulder is the second most commonly affected site. Repeated bone infarctions can also lead to chronic pain and deformity even without full avascular necrosis.
The Eyes
Sickle cell disease can damage the retina, the light-sensing tissue at the back of the eye. When small retinal blood vessels become blocked, the retina responds by growing new, fragile vessels, a process called proliferative sickle retinopathy. These abnormal vessels are prone to bleeding, which can lead to vision loss or retinal detachment. In one study of nearly 200 adults with sickle cell disease (average age 36), 28% had some stage of proliferative retinopathy. Because early retinal changes cause no symptoms, regular eye exams are important for catching and treating the condition before vision is permanently lost.
Treatment and Outlook
For decades, the mainstay of treatment has been hydroxyurea, a medication that reduces the frequency of pain crises and acute chest syndrome by boosting the production of fetal hemoglobin, a form that resists sickling. Regular blood transfusions are used for stroke prevention and severe anemia. Bone marrow transplant from a matched sibling donor has been the only established cure, but its availability has been limited.
In December 2023, the FDA approved two gene therapies for sickle cell disease in patients 12 and older. In clinical trials, 93.5% of evaluable patients who received one therapy were free from severe pain crises for at least 12 consecutive months, and 88% of patients receiving the other therapy achieved complete resolution of pain episodes. Both treatments work by modifying a patient’s own stem cells, either by editing the gene responsible for hemoglobin production or by adding a functional copy of the gene. While these therapies represent a potential cure, they require intensive chemotherapy conditioning beforehand and are currently available at a limited number of specialized centers.