How sickle cell disease damages red blood cells

Sickle cell disease causes anemia because the red blood cells break down much faster than the body can replace them. In sickle cell disease, a genetic mutation changes the shape of hemoglobin — the protein inside red blood cells that carries oxygen. Instead of staying round and flexible, the cells become rigid and curved, like a sickle or crescent moon.

These sickled cells get stuck in blood vessels, blocking blood flow and causing pain and organ damage. But before that happens, the body's spleen recognizes them as damaged and destroys them. A healthy red blood cell lives about 120 days. A sickled cell lives only 10 to 20 days. The bone marrow tries to make new cells fast enough to keep up, but it cannot produce them quickly enough to replace what is being destroyed.

The result is anemia — not enough healthy red blood cells circulating to carry oxygen to the body's tissues. This is why people with sickle cell disease feel tired, short of breath, and weak. Their organs are not getting the oxygen they need.

Key Takeaways

  • Sickle cell disease causes a genetic change that makes red blood cells rigid and curved instead of round and flexible.
  • The spleen destroys sickled cells much faster than normal cells, reducing their lifespan from 120 days to 10 to 20 days.
  • The bone marrow cannot produce new red blood cells fast enough to replace the ones being destroyed, leading to anemia.
  • Chronic hemolysis — the constant breakdown of red blood cells — is the main reason people with sickle cell disease develop anemia.

The role of hemoglobin in sickle cell anemia

Hemoglobin is made of four protein chains. In sickle cell disease, one amino acid (a building block of protein) is different in the beta-globin chain. This single change causes hemoglobin molecules to stick together when oxygen levels drop, forming long fibers inside the cell. These fibers distort the cell into that characteristic sickle shape.

Normal hemoglobin stays dissolved in the cell and does not polymerize — it does not form these chains. This is why people without sickle cell disease do not have this problem. The abnormal hemoglobin in sickle cell disease is called hemoglobin S, while the normal version is hemoglobin A.

People with sickle cell trait carry one copy of the sickle gene and one normal gene. They make both hemoglobin A and hemoglobin S, but usually have enough normal hemoglobin to prevent most cells from sickling. People with sickle cell disease carry two copies of the sickle gene and make mostly hemoglobin S, so sickling happens regularly.

Why the spleen destroys sickled cells so quickly

The spleen is an organ that filters the blood and removes old or damaged cells. When red blood cells sickle, their surface changes in ways that signal to the spleen that something is wrong. The spleen recognizes them as abnormal and breaks them down.

This process is called hemolysis — the destruction of red blood cells. In sickle cell disease, hemolysis happens constantly because sickling is happening constantly. The spleen works overtime trying to remove damaged cells, which is why it often becomes enlarged in people with sickle cell disease. Over time, the spleen can become so damaged from this work that it stops functioning well, which actually increases the risk of certain infections.

The body tries to compensate by telling the bone marrow to work faster and produce more red blood cells. You can see this effort in blood tests: people with sickle cell disease usually have a higher reticulocyte count, meaning more young, newly made red blood cells are circulating. But even this increased production cannot keep pace with the destruction.

The bone marrow's struggle to keep up

The bone marrow is the spongy tissue inside bones where all blood cells are made. It contains stem cells that divide and mature into red blood cells, white blood cells, and platelets. In sickle cell disease, the bone marrow is working at maximum capacity, trying to produce enough red blood cells to replace the ones being destroyed.

This constant demand exhausts the bone marrow over time. The marrow needs adequate supplies of iron, vitamin B12, and folate to make red blood cells efficiently. People with sickle cell disease often need higher amounts of these nutrients because they are making so many cells. If these nutrients run low, red blood cell production slows even further, making the anemia worse.

Additionally, some people with sickle cell disease develop aplastic crisis — a temporary period when the bone marrow stops making red blood cells altogether, usually triggered by a viral infection. During this crisis, anemia becomes severe very quickly because cells are being destroyed but not replaced at all.

How chronic hemolysis affects the whole body

When red blood cells break down, they release their contents into the bloodstream. One of those contents is bilirubin, a yellow pigment. The liver normally processes bilirubin and removes it from the body, but in sickle cell disease, so much bilirubin is being released that the liver cannot keep up. This causes jaundice — a yellowing of the skin and eyes — and increases the risk of gallstones.

The constant hemolysis also releases hemoglobin into the urine, which can damage the kidneys over time. Free hemoglobin in the blood can damage blood vessel linings and contribute to organ complications. The body also loses iron when red blood cells break down, and iron is essential for making new hemoglobin. This creates a cycle where the body is losing the very nutrients it needs to fight the anemia.

The chronic anemia itself means tissues throughout the body are not getting enough oxygen. The heart has to work harder to pump blood faster to try to deliver oxygen. Over years, this extra work can lead to heart problems. The brain, bones, lungs, and kidneys all suffer from chronic low oxygen, which is why sickle cell disease affects so many organ systems.

The difference between acute and chronic anemia in sickle cell disease

People with sickle cell disease live with chronic anemia all the time — their hemoglobin and red blood cell counts are always lower than normal. This is their baseline. Their bodies adapt somewhat to this chronic low oxygen state, though the adaptation is incomplete and causes ongoing damage.

But sickle cell disease can also cause acute anemia — a sudden, severe drop in red blood cells. This can happen during a vaso-occlusive crisis (when sickled cells block blood vessels), during an infection, or during an aplastic crisis. Acute anemia develops over days or even hours and causes more severe symptoms: extreme fatigue, severe shortness of breath, dizziness, and chest pain. Acute anemia may require a blood transfusion.

Doctors monitor anemia in sickle cell disease by checking hemoglobin levels regularly. A person without sickle cell disease typically has a hemoglobin level of 12 to 16 grams per deciliter of blood. People with sickle cell disease usually have levels between 7 and 10 grams per deciliter. Doctors watch for sudden drops below a person's baseline, which signals acute anemia and may require urgent treatment.

Treatment approaches for sickle cell anemia

There is no way to stop the genetic mutation that causes sickle cell disease, but several treatments can reduce hemolysis and improve anemia. Hydroxyurea is a medication that increases the amount of fetal hemoglobin (a type of hemoglobin made during fetal development) in red blood cells. Fetal hemoglobin does not polymerize the way hemoglobin S does, so it prevents sickling. Taking hydroxyurea regularly reduces the number of sickle crises and can improve hemoglobin levels.

Newer medications like voxelotor and crizanlizumab work differently. Voxelotor changes the shape of red blood cells slightly so hemoglobin S is less likely to polymerize. Crizanlizumab reduces the stickiness of sickled cells so they are less likely to block blood vessels. These medications can reduce hemolysis and improve anemia without the side effects of hydroxyurea.

Blood transfusions are used when anemia becomes severe or during acute crises. A transfusion replaces destroyed red blood cells with healthy ones from a donor. However, repeated transfusions carry risks, including iron overload and immune reactions, so they are used when the benefit outweighs these risks.

Bone marrow or stem cell transplant can cure sickle cell disease in some people, but it requires finding a matched donor and carries significant risks. It is usually considered for children or young adults with severe disease and a well-matched sibling donor.

Frequently Asked Questions

Can someone with sickle cell disease have normal hemoglobin levels?

No. People with sickle cell disease will always have lower hemoglobin and red blood cell counts than people without the disease because hemolysis is constant. Treatments can improve these levels and reduce symptoms, but they cannot bring hemoglobin to the normal range.

Does sickle cell trait cause anemia?

Sickle cell trait usually does not cause anemia. People with trait have one sickle gene and one normal gene, so they make enough normal hemoglobin to prevent most cells from sickling. They may have mild anemia in rare cases, but it is not the defining feature of trait.

Why do people with sickle cell disease need folic acid supplements?

The bone marrow uses folic acid to make new red blood cells. Because the bone marrow is working constantly to replace destroyed cells, it uses folic acid much faster than normal. Supplements ensure the marrow has enough folic acid to keep up with production demands.

Can transfusions cure the anemia in sickle cell disease?

Transfusions improve anemia temporarily by adding healthy red blood cells to the bloodstream, but they do not cure it. The transfused cells eventually break down like the person's own cells, and the anemia returns. Transfusions are a treatment, not a cure.

Is the anemia in sickle cell disease the same as iron deficiency anemia?

No. Iron deficiency anemia happens when the body does not have enough iron to make hemoglobin. Sickle cell anemia happens because red blood cells are being destroyed faster than they can be replaced, regardless of iron levels. The causes are different, so the treatments are different.