Sickle Cell Disease Explained: Why Red Blood Cells Sickle and Cause a Crisis

Sickle cell disease is often introduced as the condition that makes red blood cells turn into a sickle shape. That is true, but it does not really explain why patients become anaemic, why a painful crisis can be so severe, or why the condition can affect organs throughout the body.

The useful bit is understanding what is happening inside the red blood cell first. Once that clicks, the rest of the condition is much easier to follow.

What actually makes the cell sickle?

Normal red blood cells are flexible biconcave discs packed with haemoglobin. Their flexibility lets them squeeze through tiny capillaries without becoming permanently damaged.

In sickle cell disease, an inherited change affecting beta-globin leads to the production of haemoglobin S (HbS). When HbS is deoxygenated, the molecules can polymerise, forming long rigid structures inside the red cell. The cell becomes less flexible and can take on the characteristic sickled shape.

At first, some of this change can reverse when the cell is reoxygenated. Repeated cycles of sickling, however, damage the cell membrane. Eventually, some red cells become persistently rigid and fragile.

Think of it as: HbS becomes deoxygenated → HbS polymerises → the red cell stiffens and changes shape → repeated sickling damages the cell.

That damage creates two major problems at the same time: red cells are destroyed too quickly, causing haemolysis, and blood flow through the microcirculation becomes disrupted.

Why does it cause pain and anaemia?

A vaso-occlusive crisis is more complicated than sickled cells simply getting stuck. Rigid red cells have difficulty moving through small vessels, but inflammation, endothelial activation and increased adhesion between blood cells and the vessel wall also contribute. Microvascular blood flow is disrupted and tissues can become relatively ischaemic.

That is where the severe pain comes from. Ischaemia and inflammation stimulate pain pathways, and reduced oxygen tension can encourage further HbS polymerisation. The process can therefore feed into itself.

At the same time, damaged sickled cells do not survive for as long as normal red blood cells. Their premature destruction is called haemolysis. The bone marrow tries to compensate by increasing red-cell production, but it may not keep up, resulting in chronic haemolytic anaemia.

This is why the blood results start to make sense rather than looking like a random collection of abnormalities. Haemoglobin may be chronically low, reticulocytes can be raised because the marrow is trying to replace lost cells, and bilirubin may rise as haemoglobin is broken down. Chronic bilirubin turnover also increases the risk of pigment gallstones.

One useful placement point is that a patient with sickle cell disease may normally live with a haemoglobin level that would look low in somebody else. Their own baseline matters. A significant fall from that baseline can be more informative than looking at the number in isolation.

When a painful crisis is not just pain

An acute painful sickle cell episode, often called a vaso-occlusive crisis, can cause severe pain in the back, limbs, chest, abdomen or elsewhere. Episodes may be associated with dehydration, infection, cold exposure, temperature changes, stress or significant exertion, although sometimes there is no obvious trigger.

For nurses, the important point is not to stop the assessment at “this is their usual sickle pain”. Pain needs prompt treatment, but the patient also needs assessment for complications and other causes of deterioration.

Acute chest syndrome is one of the complications you particularly need to recognise. A patient may develop chest pain, fever, cough, breathlessness, hypoxaemia or other respiratory deterioration. The presentation can overlap with pneumonia and other chest conditions, so new chest symptoms or worsening respiratory observations need urgent assessment and escalation.

Infection also deserves attention. Repeated sickling and infarction can progressively damage the spleen and lead to functional asplenia. Because the spleen plays an important role in immune defence, patients can be more vulnerable to serious infection. Fever should therefore be taken seriously rather than dismissed as an incidental finding.

The same underlying problems with haemolysis and blood flow help explain other complications of sickle cell disease, including stroke, renal damage, retinopathy, avascular necrosis, priapism and gallstones. Splenic sequestration, particularly in children, can cause blood to pool rapidly within the spleen and lead to acute anaemia and circulatory compromise.

What should you be thinking about on placement?

If you meet a patient with sickle cell disease, listen to them. Many patients know their usual pain pattern, baseline observations and treatments extremely well. If they tell you something feels different from their normal crisis, that information matters.

Your assessment will depend on the clinical setting and your level of supervision, but you may be involved with observations, oxygen saturation monitoring, pain assessment and reassessment, fluid balance, blood sampling and medicines administration.

Features that need prompt review include new respiratory symptoms, falling oxygen saturations, fever or signs of infection, new neurological symptoms, a sudden worsening of anaemia or pallor, severe uncontrolled pain, significant abdominal pain or enlargement, priapism, or a patient who simply appears acutely unwell.

NICE treats an acute painful sickle cell episode presenting to hospital as an acute medical emergency. Analgesia should be offered promptly, pain should be reassessed and observations should include oxygen saturation. Previous effective analgesia and the patient's individual care plan should be taken into account. Oxygen is given when clinically indicated rather than automatically to every patient having a painful episode.

Longer-term treatment is individualised. Hydroxycarbamide can reduce sickling-related complications in appropriate patients. Blood transfusion or exchange transfusion may be required for specific indications and complications, but transfusion is not routine treatment for every uncomplicated painful crisis. Specialist haematology guidance and local policy are important.

Can sickle cell disease actually be cured?

For some people, yes. Haematopoietic stem cell transplantation has long offered the possibility of cure, but it requires a suitable donor and carries significant risks. Gene therapy has now created another potentially curative route for carefully selected patients.

A recent example is Daniel Cressy, a 23-year-old man in Louisiana who became the first patient in the state to be described by his clinical team as functionally cured of sickle cell disease after treatment with exagamglogene autotemcel, known as Casgevy. His own blood-forming stem cells were collected and genetically edited using CRISPR/Cas9 technology. After conditioning chemotherapy, the edited cells were infused back into his body. The treatment is designed to increase fetal haemoglobin (HbF), which reduces red-cell sickling. His cells were infused in March 2026 and, by June 2026, his hospital reported that his haemoglobin was the highest it had been in his life.

The wording “functionally cured” matters. It does not mean that sickle cell disease now has a simple or universally available cure, and long-term follow-up remains essential. Gene therapy involves intensive treatment, including stem-cell collection and chemotherapy, and eligibility is restricted.

This development is relevant in UK practice too. NICE recommends exagamglogene autotemcel with managed access for certain people aged 12 years and over with severe sickle cell disease and recurrent vaso-occlusive crises when a stem cell transplant is appropriate but a matched related donor is unavailable. NICE describes exa-cel as a possible cure, while also recognising uncertainty about how well its effects will persist in the long term.

For a student nurse, the important change is this: sickle cell disease should no longer be understood only as a lifelong condition managed with analgesia, hydroxycarbamide and transfusion. For a small, carefully selected group of patients, modern stem-cell and gene-editing therapies may fundamentally change the course of the disease.

Sickle cell trait is different

Sickle cell trait is not the same as sickle cell disease. A person with the trait carries one sickle haemoglobin gene and one usual beta-globin gene and generally does not experience the clinical syndrome seen in sickle cell disease.

If both parents carry a sickle cell gene, each pregnancy has a 1 in 4 chance of the child having sickle cell disease, a 1 in 2 chance of the child being a carrier, and a 1 in 4 chance of inheriting neither sickle gene.

If you remember one chain, make it this:
Inherited beta-globin change → HbS → deoxygenated HbS polymerises → red cells become rigid and damaged → haemolysis plus disrupted microvascular blood flow → anaemia, pain and organ complications.

That is the physiology underneath the sickle-shaped cell, and it is the part that makes the clinical picture make sense.

References

National Institute for Health and Care Excellence (NICE). Sickle cell disease: managing acute painful episodes in hospital (CG143). London: NICE.

National Institute for Health and Care Excellence (NICE) (2025). Exagamglogene autotemcel for treating severe sickle cell disease in people 12 years and over (TA1044). London: NICE.

NHS. Sickle cell disease.

NHS England (2025). Sickle cell disease: what every clinician needs to think about.

Manning Family Children’s (2026). Manning Family Children’s makes history as Louisiana’s first Sickle Cell Disease gene therapy patient rings the bell, marking his functional cure.

University College London Hospitals NHS Foundation Trust. Sickle cell disorder in adults. The Red Cell Network.