Sickle cell disease

Sickle cell disease is a group of inherited conditions affecting hemoglobin, the protein inside red blood cells that carries oxygen. It is not a cancer, and it is not something acquired during life — a person is born with it.

It comes from changes in the HBB gene, which carries the instructions for part of the hemoglobin molecule. The change produces hemoglobin S instead of the usual adult hemoglobin A. Under low-oxygen conditions, hemoglobin S forms stiff strands inside the red cell, so the cell turns rigid and crescent-shaped instead of staying a flexible disc.

Which genotype someone has matters, and it is worth knowing the name of yours. HbSS means two copies of the sickle change and was historically called sickle cell anemia; it is generally the most severe. HbSC pairs a sickle change with a hemoglobin C change. HbS/beta-thalassemia splits again into HbS/beta-zero, which behaves much like HbSS, and HbS/beta-plus, which is often milder.

Then there is the point this subject gets wrong more than any other. Sickle cell TRAIT — genotype HbAS — means inheriting the sickle change from one parent and a normal hemoglobin gene from the other. The NHLBI describes people with trait as making about 60% normal hemoglobin and 40% sickle hemoglobin, and typically having no symptoms. Trait is a carrier state. It is not a mild version of the disease.

Sickle cell disease is inherited in what is called an autosomal recessive pattern: a child develops it only by inheriting an affected hemoglobin gene from each parent. Nothing the parents did or did not do causes it. It is not infectious and not related to lifestyle.

Where both parents carry sickle cell trait, each pregnancy independently carries a 1-in-4 chance of a child with the disease, a 1-in-2 chance of a child with trait, and a 1-in-4 chance of a child with neither. The word doing the work there is “independently” — families very often read it as one in four of their children, and that is not what it means.

The sickle change is common in regions where malaria has historically been endemic, and carrying one copy is understood to have offered some protection against it. That is context for why the gene persists — not a benefit of the disease.

Two things follow from the change in the cell’s shape. Sickled cells break down early, which causes a chronic anemia — fatigue, breathlessness, jaundice. And they obstruct small blood vessels, which causes pain and, over years, injury to organs.

The blockages produce what is called a vaso-occlusive crisis, or a pain crisis. The NHLBI describes it as often-serious pain, and the NHS describes episodes lasting days or weeks. It is the defining lived experience for many people with the condition, and it is completely invisible to anyone looking at them.

Acute chest syndrome is a medical emergency involving the lungs, treated in hospital with antibiotics, oxygen and sometimes transfusion. Stroke risk in children is a defining feature of the condition in childhood, and it is the reason children are offered a scan called transcranial Doppler ultrasound, which measures how fast blood is moving in the arteries of the brain and identifies children who would benefit from preventive treatment.

The spleen, which helps fight certain bacteria, is damaged early in life in many children, which is why penicillin and vaccinations start in infancy. Painful swelling of the hands and feet is often one of the first signs in a baby. Prolonged painful erection is a recognised urological emergency in boys and men.

Severity varies enormously — between genotypes, between people with the same genotype, and across one person’s life. Some people have mild symptoms with little impact; others face serious complications.

Most treatment is ongoing rather than one-time. Hydroxyurea, called hydroxycarbamide in the UK, is a daily tablet that raises the level of fetal hemoglobin — the kind made before birth, which does not sickle. In a 1995 multicentre trial it reduced pain crises by a mean of 2.80 per year, and long-term follow-up has shown reduced acute chest syndrome and reduced mortality.

Hydroxyurea has a genotype-specific evidence base: it is recommended for HbSS and HbS/beta-zero from six to nine months of age. It also has real costs — it can lower blood counts and needs regular monitoring, it can cause mouth ulcers, nausea, rash and skin darkening, it reduces sperm counts in males in a way that may persist beyond a year, and it is not used in pregnancy or breastfeeding. A meta-analysis across 3,278 patients found no accumulated evidence linking it to a second cancer.

Blood transfusion is used for severe anemia, for stroke prevention and as emergency treatment in acute chest syndrome. Repeated transfusion brings its own problems — iron builds up and has to be removed with chelation, and the immune system can start reacting against donated red cells.

A transplant using another person’s blood-forming cells has the longest follow-up of the intensive options, and is most established from a matched sibling. Two gene therapies were approved in 2023 — exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) — and both use the person’s own cells, edited in a laboratory and given back. No donor is involved in either.

All three intensive routes require conditioning chemotherapy first, with the infertility risk that carries. Both gene therapy labels direct that fertility preservation be discussed beforehand, and Lyfgenia carries a boxed warning.

The diagnosis often arrives at birth through newborn screening, before there is any symptom at all. So some of the people reading this are parents of a well-looking baby rather than anyone in crisis.

Care is lifelong and shaped like a calendar rather than an episode: daily medicine, penicillin from infancy, vaccinations, brain scans through childhood, transfusion appointments, iron chelation, specialist review. It is a management burden that does not end.

Geography largely determines which of these a person will ever be offered. Most affected children are born in sub-Saharan Africa, while universal newborn screening, stroke-prevention programmes, transplant centres and gene therapy are concentrated elsewhere. A reader in Lagos and a reader in Leeds are reading about different available worlds.

What that gap is made of is worth being precise about, because it is not exotic technology. Jamaica’s newborn screening programme reduced childhood mortality in the screened population from 30% to under 5%. Screening plus penicillin plus follow-up is not a frontier — it is a system.

For sickle cell disease, a donor from a registry is not the usual route. Where a transplant happens at all, it is overwhelmingly from a relative — and that is the fact this page has to lead with, because a bone marrow charity has an obvious incentive to tell you otherwise.

You will sometimes see sickle cell used as the reason to recruit more donors of colour to a registry. Registry under-representation is real and it matters a great deal for other conditions — but presenting it as the sickle cell bottleneck turns a structural inequity in access into a story about a shortage of willing volunteers, and that is not what the evidence shows.

What the evidence does show the bottlenecks to be: newborn screening coverage, diagnosis, access to hydroxyurea and safe transfusion, tissue typing, referral, transplant-centre capacity, financing, and long-term follow-up — concentrated almost exactly where the disease is not.

A full brother or sister has roughly a 1-in-4 chance of being HLA-identical, if such a sibling exists at all. That does not mean the other three-quarters need a registry donor: half-matched relatives, cord blood and mismatched unrelated donors are all routes, and many people never pursue a transplant.

One thing specific to inherited conditions: a relative may themselves carry sickle trait or another hemoglobin variant, so a donor’s hemoglobin status is part of the specialist evaluation. That cuts both ways and it is not something a family can work out from a web page.