Sickle cell disease
Sickle cell disease has a starting scene in Chicago. In December 1904, Walter Clement Noel, a 20-year-old first-year dental student from Grenada, was admitted to Chicago Presbyterian Hospital with anaemia. Cells in his blood would eventually give a whole group of inherited blood disorders its name. His case raises questions that medicine spent the next century answering. What turns a round, flexible blood cell into a rigid crescent? Why would nature preserve a gene that so often shortens life? And how did a disease first noticed under a single microscope come to be treated by editing a patient's own DNA?
On chromosome 11 sits the HBB gene, which carries the recipe for β-globin, one of the protein chains that make up haemoglobin. Haemoglobin ferries oxygen inside red blood cells, from the lungs to the tissues, or from the placenta in a foetus. Each molecule combines four globin subunits. In adults, haemoglobin A, built from two alpha and two beta chains, accounts for over 97% of the total. Foetal haemoglobin uses gamma chains instead of beta chains and dominates until about 6 weeks of age.
At position 6 of the β-globin chain, a single swapped building block changes everything. A one-nucleotide mutation puts the amino acid valine where glutamate belongs. The resulting protein is called haemoglobin S, or HbS. With plenty of oxygen around, it behaves almost normally. Without oxygen, its deoxygenated form exposes a water-repelling patch, and the molecules link into long, stiff chains.
Seconds after oxygen levels fall, those chains push a smooth, doughnut-like cell into a rigid sickle shape. Exercise, stress, altitude and dehydration can all bring on low oxygen. If sickling happens in the veins, after blood has already passed the capillaries, the organs are spared, and the cells relax again when the lungs re-oxygenate them. Repeated switching injures the cell membrane, though, and eventually the cell stays sickled for good.
Healthy red blood cells work for 90-120 days, while sickled cells last only 10-20 days. The bone marrow cannot replace them fast enough, and the destruction itself, called haemolysis, produces the anaemia. Bursting cells also release free heme into the bloodstream. Heme is a powerful oxidising molecule, and it doubles as an alarm signal that raises the risk of inflammation and blockages.
Each child of two carriers faces a 25% chance of disease, a 25% chance of no sickle gene and a 50% chance of being a carrier. The disease follows an autosomal recessive pattern, so both copies of the gene must carry the mutation. A carrier makes a mix of normal HbA and HbS. Carriers usually have few symptoms, and they may notice trouble only at altitude or when severely dehydrated.
Five named variants of the mutation, called Cameroon, Senegal, Benin, Bantu and Saudi-Asian, suggest it may have arisen separately in different regions. The Senegal and Saudi-Asian variants come with higher levels of foetal haemoglobin and tend toward milder disease. That pattern of independent origins leaves a puzzle, because a gene that harms so many of its owners should fade away.
In 1954, researchers established that carriers of the sickle gene are partly shielded against malaria. The finding explained why the gene persists wherever malaria has threatened populations. Carriers who catch malaria are less likely to become severely ill than people with ordinary haemoglobin. Two mechanisms are described. The parasite struggles to grow and reproduce inside a carrier's red cells. And infected carrier cells show signs of damage, so the spleen detects and destroys them.
People with full sickle cell disease are also less likely to be infected. Once infected, though, they face a greater risk of life-threatening anaemia. The shorter lives of people with two sickle genes should weed the trait out. The advantage enjoyed by carriers keeps it in circulation instead, which is natural selection at work. Southern Europe once had endemic malaria and was declared free of it in the mid-20th century, apart from rare sporadic cases. Among the Tharu people of Nepal and India, the rate of malaria is sevenfold lower despite their living in a malarial zone.
The current estimate is about 7.7 million people with sickle cell disease worldwide. It directly causes an estimated 34,000 deaths a year and contributes to a further 376,000. About 80% of cases are believed to occur in sub-Saharan Africa. The rest are found in parts of India, Southern Europe, West Asia and North Africa, and among people of sub-Saharan African origin living elsewhere. A separate estimate put deaths in 2015 at about 114,800.
In Nigeria, a World Health Organization report dated 2006 estimated that around 2% of newborns are affected. That adds up to 150,000 affected children every year, and 24% of Nigeria's population carries the gene. Carrier frequency runs from 10-40% across equatorial Africa, falls to 1-2% on the North African coast and drops below 1% in South Africa. Uganda has the fifth-highest burden of the disease. One study counts about 20,000 babies born with it each year. Among the Baamba people of Uganda, carrier frequency reaches 45%.
In the United States, about 100,000 people live with the disease, or one in 3,300. One in 365 African-American children is born with it, and about 8% of African Americans are carriers. By 2016, all 50 states included sickle cell screening in newborn testing. Migration has changed the picture in Europe too. In France, the disease has become the most common genetic condition, at one birth in 2,415, ahead of cystic fibrosis at one in 5,014. In the United Kingdom, between 12,000 and 15,000 people are thought to be affected, with an estimated 250,000 carriers in England alone.
In Saudi Arabia, 4.2% of people carry the trait, and the Eastern province reaches roughly 17%. A mandatory premarital test using haemoglobin electrophoresis began there in 2005. Bahrain began screening all pregnant women in 1992 and passed a law in 2004 requiring free counselling for couples planning to marry. Central India shows prevalence of 9.4-22.2% in endemic areas of Madhya Pradesh, Rajasthan and Chhattisgarh. In Jamaica, 10% of the population carries the gene.
Where healthcare infrastructure is missing, an estimated 50-90% of children born with the disease die before the age of 5. With good care, median life expectancy lies between 58 and 66 years. In 2010-2020, life expectancy was 43 years in the United States and 67 years in the United Kingdom.
Trouble typically begins around 5 to 6 months of age. In the first year of life, the most common problem is dactylitis, also called hand-foot syndrome, which brings pain and swelling in a baby's hands and feet. Pallor, jaundice and fatigue can also appear as signs of anaemia. In children older than 2, dactylitis almost never occurs. The usual first sign becomes a painful episode, and a slightly less common one is acute chest pain.
The vaso-occlusive crisis is the best-known event, and it brings extreme pain in the chest, back, legs or arms. Sickled cells jam capillaries, starving an organ of blood and causing ischaemia, pain, tissue death and often lasting damage. Cold, physical or mental stress and dehydration can set one off, because each narrows blood vessels. Frequency, severity and duration vary widely from person to person. A crisis in the lungs or the penis is treated as an emergency with red blood cell transfusions.
The median age of a first splenic sequestration crisis is 1.4 years. The spleen filters blood, so sickled cells block its filter, and the organ swells and fills with blood. That causes a sudden fall in circulating haemoglobin and potentially deadly anaemia. Left-sided pain, a swollen spleen, fatigue, dizziness, rapid heartbeat and pale skin are the warning signs. By the age of 5, repeated episodes scar the spleen until it shrinks and stops working. Without a working spleen, children become prone to bacterial infections, especially Streptococcus pneumoniae and Haemophilus influenzae.
Acute chest syndrome accounts for about 25% of deaths in people with sickle cell disease. After a pain crisis, it is the second most common reason for hospital admission. Wheezing, chest pain, fever, hypoxemia and a shadow on the chest x-ray mark it. Most cases begin as a vaso-occlusive crisis and then spread to the lungs. Infection or clots travelling from other organs may be the spark.
Parvovirus B19 sets off the aplastic crisis by invading the cells that give rise to red blood cells and destroying them. Production almost stops for two to three days. In healthy people, that pause hardly matters, but sickle cells die so quickly that anaemia becomes abruptly life-threatening. Recovery takes four to seven days, and most patients are managed with supportive care. Some need a transfusion.
Between 10% and 15% of children with sickle cell disease have strokes. Silent strokes, which cause no immediate symptoms but still damage the brain, are probably five times as common as symptomatic ones. Gallstones, bone death in the hip and other joints, and bone infections from Staphylococcus aureus or Salmonella can follow. Kidney failure, disabling leg ulcers and eye damage that can end in blindness are further risks. Pregnancy brings the threats of growth restriction in the foetus, spontaneous abortion and pre-eclampsia. Many patients also live with chronic pain that goes unreported.
Pulmonary hypertension appears in 21% of children and 30% of adults when they are tested. It is linked to a shorter walking distance and higher mortality.
The first trimester is early enough for chorionic villus sampling, a technique that can diagnose sickle cell disease before birth. Prenatal screening begins with a questionnaire about the health of the parents and close relatives. Genetic testing can then use either a blood sample from the foetus or a sample of amniotic fluid. After birth, a heel prick a few days later collects a small drop of blood that conclusively checks for sickle cell disease and other inherited conditions. In the United States, the baby must have been eating for at least 24 hours before the test. Some states ask for a second test at two weeks to confirm the result.
Blood donors in high-risk groups in the United Kingdom are also screened. Donors found to be carriers are told, and their blood is not used for transfusions to patients with sickle cell disease. Pregnant women and both partners in a couple are offered screening, since many adults do not know whether they carry the trait.
Two tests are specific to the disease. A blood smear, with stained blood spread across a glass slide, lets a microscope reveal sickled cells but misses carriers. A solubility test exploits the fact that HbS dissolves less easily than normal haemoglobin. It is highly reliable, yet it cannot separate full disease from carrier status.
Other tests look at haemoglobin more broadly. In haemoglobin electrophoresis, haemoglobin is placed in a porous gel and exposed to an electrical field, which separates the normal and abnormal types. Isoelectric focusing sorts molecules by the pH at which they carry no net charge, producing sharp stationary bands. High-performance liquid chromatography is automated and can distinguish most types, including carriers. DNA analysis using PCR confirms a result and can identify subtypes and combined haemoglobin disorders. A simple, cheap test usually comes first, with the complex one used to confirm a positive.
Genetic counsellors help families weigh the limits and logistics of testing, and what results could mean for them. Counselling works best before a child is conceived. Options raised can include adoption, eggs or sperm from a healthy donor, and in-vitro fertilisation combined with pre-implantation diagnosis of the embryos.
Penicillin taken daily during the first 5 years of life guards against pneumococcal infection, a leading cause of death among children with the disease. Routine vaccinations add further protection, since infections can trigger a crisis. Everyday habits matter too. Staying hydrated, avoiding exhaustion and steering clear of high mountains or unpressurised aircraft all lower the risk of sickling. Alcohol can dehydrate, and smoking can trigger acute chest syndrome. Breathing exercises can help with stress.
Folic acid is sometimes recommended to support new red cell production. A Cochrane review in 2016 found that "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear", because evidence was lacking.
Hydroxyurea, also called hydroxycarbamide, was the first drug approved for sickle cell disease, and it had earlier been used as a chemotherapy agent. It reactivates foetal haemoglobin production in place of the HbS that causes sickling. It also reduces sticky adhesion molecules on cells and encourages the release of nitric oxide, which helps blood flow. Some worry that long-term use may be harmful, and a Cochrane review in 2022 found a weak evidence base.
In 2019, the United States granted accelerated approval to voxelotor, and the European Medicines Agency followed in 2021. Pfizer later withdrew it worldwide after registries and trials showed an increased risk of death among other problems. Crizanlizumab, approved in the United States in 2019 for people 16 and older, met a similar fate. Its authorisation was withdrawn in the United States, United Kingdom and European Union over poor evidence of effectiveness.
At home, a crisis may be handled with rest, fluids and over-the-counter paracetamol or ibuprofen. Severe cases may need prescription opioids such as codeine or morphine.
Transfusions come in two forms. A simple top-up transfusion infuses donor red cells to ease anaemia, raise tissue oxygen and cut the risk of sickling, and it can prepare a patient for surgery or pregnancy. An exchange transfusion removes the patient's blood, extracts the sickled cells, and returns the blood with healthy donor cells added. Emergencies, severe cases and support during pregnancy call for it.
Transcranial Doppler ultrasound measures blood flow speed in the brain, and fast flow signals narrowed arteries. In children whose scans show abnormal flow, preventive transfusions reduce the risk of a first stroke or silent stroke. Damaged bone is treated by resting the joint, physical therapy, pain relief, joint replacement or bone grafting. Psychological therapies are offered alongside medicine, but their effectiveness needs further research.
Since 1991, a small number of patients have received bone marrow transplants from healthy matched donors, a high-risk procedure. Donors can be umbilical cord blood, matched relatives or matched unrelated people. Risks include graft-versus-host disease and graft failure. Any stem cell treatment first requires myeloablation, which destroys the marrow's faulty stem cells using high doses of chemotherapy, with nausea and fatigue as side effects. A long hospital stay follows while replacement cells settle into the marrow.
Gene therapy was first trialled in 2014 on a single patient. In 2023, Casgevy, also known as exa-cel, and Lyfgenia were both approved. Both start by harvesting the patient's own stem cells and modifying them in the laboratory with CRISPR gene editing. Casgevy edits the BCL11A gene, which normally suppresses foetal haemoglobin in adults, so the body makes more of the non-sickling form. Lyfgenia adds a gene for T87Q-globin, which sits alongside the sickling beta-globin and reduces sickling.
Kendric Cromer became the first commercial case in the United States in October 2024. He was discharged from Children's National Hospital. England's National Health Service planned to offer the one-off therapy from 2025.
A report in 1846 on the autopsy of an executed runaway slave may be the first modern mention of the disease. Its key finding was that the spleen was missing. African slaves in the United States were reportedly resistant to malaria but prone to leg ulcers.
In 1910, Chicago cardiologist James B. Herrick, who lived from 1861 to 1954, published the first description in the medical literature. His intern, Ernest E. Irons, who lived from 1877 to 1959, had seen "peculiar elongated and sickle-shaped" cells in the blood of Walter Clement Noel. Noel was readmitted several times over the next three years with "muscular rheumatism" and "bilious attacks". Even so, he completed his studies and returned to St. George's, the capital of Grenada, to practise dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs, in the north of Grenada.
Shortly after Herrick's report, the Virginia Medical Semi-Monthly published a case under almost the same title. Its patient had been admitted to the University of Virginia Hospital on the 15th of November 1910. Verne Mason used the name "sickle cell anemia" for the first time in 1922. Childhood problems were not reported until the 1930s, although they cannot have been uncommon in African-American populations.
Memphis physician Lemuel Diggs distinguished disease from trait in 1933. The genetics came into focus in 1949, when James V. Neel and E. A. Beet worked out how it is inherited. That same year, Linus Pauling traced the unusual chemistry of haemoglobin S to an abnormality in the molecule itself. Vernon Ingram described the molecular change in 1956. In 1954, haemoglobin electrophoresis brought the discovery of subtypes such as HbSC disease.
Large natural history and intervention studies in the 1970s and 1980s led to widespread use of prophylaxis against pneumococcal infection. Hydroxycarbamide was developed in the 1990s. In 2007, reports of a cure through bone marrow transplantation appeared. The condition has also been called drepanocytosis.
In 1970, the Black Panther Party opened dozens of free clinics across the United States that offered free sickle cell tests. Over the 1970s, thousands of people, largely African Americans, were tested at them. The clinics grew out of stigma that keeps people from needed care, which is attributed in part to racism, since most people with the disease are black. Patient advocates have complained that it draws less government and private research money than comparable rare diseases such as cystic fibrosis. Researcher Elliott Vichinsky said this points to racial discrimination or to the role of wealth in health care advocacy. In September 2017, the Social Security Administration issued a ruling explaining how it evaluates the disease in disability claims.
In Uganda, the Sickle Cell Clinic in Mulago is the country's only clinic for the disease and sees about 200 patients a day. Data on the disease there has not been updated since the early 1970s, a gap blamed on a lack of research funding. The disease contributes 25% of child mortality, and 80% of those born with it do not live past 5. Western Ugandans are more likely than Eastern Ugandans to believe it is a punishment from God or witchcraft. Others wrongly think the environment causes it, when genetics does.
Fear of being labelled or cursed leads families to hide a relative's illness. Sometimes a family's intimate relationships are avoided once a diagnosis is confirmed. Children with the disease can be rejected by peers, which may lead to emotional distress, school avoidance and weaker results. Jaundice, stunted growth and delayed puberty can make them targets for bullying.
Mothers often take the blame. If no earlier generation had the disease, they are suspected of neglecting prevention or failing to provide a healthy home. Women with the disease who become pregnant are frequently branded irresponsible and may feel ashamed and alone. Many become single mothers after partners leave, claiming they did not know. In 2013, the Uganda Sickle Cell Rescue Foundation was established to spread awareness and fight the stigma.
Television and film have taken up the subject. Bill Cosby's Emmy-winning 1972 TV movie, To All My Friends on Shore, told the story of the parents of a child with the disease. The medical drama ER touched on it in season 4 and season 15. More recent television includes the 2024 British superhero series Supacell, the 2024 period drama Lady in the Lake and the 2025 drama The Pitt. Noah Wyle, who plays Dr. Michael "Robby" Robinavitch in The Pitt, has spoken about racism and the quality of care patients receive.
Films include the 1973 A Warm December, the 1996 Nigerian drama Mortal Inheritance and the Genie Award-winning 2008 Canadian drama Nurse.Fighter.Boy. Others are the 2017 animated documentary Spilled Milk, the 2020 Nigerian drama Strain, the 2022 animated short The Park Bench and the 2023 film Transformers: Rise of the Beasts. Visual artist Hertz Nazaire, a Haitian-American writer who lived with sickle cell disease, used his art to fight stigma and press for better access to care.
Updated
Common questions
What is sickle cell disease?
Sickle cell disease is a group of inherited blood disorders in which abnormal haemoglobin makes red blood cells take a sickle shape. The rigid cells cannot bend through capillaries and cause blockages. The most common type is sickle cell anaemia.
What causes sickle cell disease?
Sickle cell disease occurs when a person inherits two abnormal copies of the β-globin gene, one from each parent. The mutation replaces glutamate with valine at position 6 of the β-globin chain and produces haemoglobin S. It follows an autosomal recessive pattern of inheritance.
Why is sickle cell disease common in regions with malaria?
Carriers of one abnormal gene are partly protected against severe malaria, so the trait persists where malaria has been common. This protection was established in 1954. The shorter lives of people with two copies are offset by the advantage to carriers, an example of natural selection.
How is sickle cell disease diagnosed?
Sickle cell disease is diagnosed with a blood test. A heel prick a few days after birth screens newborns, and chorionic villus sampling can diagnose it in the first trimester of pregnancy. Haemoglobin electrophoresis, high-performance liquid chromatography and PCR-based DNA analysis can identify and confirm it.
What are the treatments for sickle cell disease?
Treatment includes vaccinations, daily penicillin in early childhood, hydration, pain medication, blood transfusions and hydroxyurea. In 2023, two gene therapies, Casgevy and Lyfgenia, were approved. Bone marrow transplants from matched donors are another high-risk option.
Who first described sickle cell disease?
American physician James B. Herrick first described sickle cell disease in the medical literature in 1910. His intern, Ernest E. Irons, saw the sickle-shaped cells in the blood of Walter Clement Noel, a dental student from Grenada. Verne Mason first used the name sickle cell anemia in 1922.
How many people have sickle cell disease worldwide?
Sickle cell disease is estimated to affect about 7.7 million people worldwide. About 80% of cases are believed to occur in sub-Saharan Africa. It directly causes an estimated 34,000 deaths a year.
What is the life expectancy with sickle cell disease?
With good healthcare, median life expectancy with sickle cell disease is between 58 and 66 years. In 2010-2020, life expectancy was 43 years in the United States and 67 years in the United Kingdom. Where healthcare infrastructure is missing, an estimated 50-90% of affected children die before age 5.
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