Sickle cell disease: causes, complications, and cures

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What is sickle cell disease?

Sickle cell disease (SCD) is a group of red blood cell disorders caused by misshapen hemoglobin, the protein in red blood cells that delivers oxygen throughout the body. Normal red blood cells are disk shaped, which allows them to flow smoothly through blood vessels. In contrast, the SCD genetic mutation causes the red blood cells to be crescent or sickle shaped. These sickle cells become rigid and sticky inside of the blood vessels, which blocks and slows blood flow to the body.

Who is at risk?

SCD impacts nearly 100,000 Americans. In the United States, SCD primarily impacts Black or African Americans, but Hispanic-Americans are also at risk. Children diagnosed with SCD must inherit one copy of the sickle cell gene from each of their parents. If the child only inherits one copy of the trait, they have sickle cell trait. People with sickle cell trait do not normally show symptoms of the disease since they make both normal and sickle cell hemoglobin. However, they are carriers for the disease and may pass it on to their own children.

How is it diagnosed?

Diagnostic screening for SCD can occur both before and after the child is born. Prenatal screening involves testing the amniotic fluid (amniocentesis) or placenta tissue (chorionic villus sampling) for the sickle cell gene. Newborns in the US are checked for SCD during typical newborn screening tests. The hemoglobin from drops of blood from a heel prick are tested in a lab to diagnose this condition. Babies with SCD are at increased risk of infections, so early diagnosis and treatment is essential to limit complications.

What are the symptoms?

The lifespan of a sickle cell is between 10 and 20 days, which is much shorter than the 120 day lifespan of a red blood cell. This may lead to a shortage of blood, known as anemia, where the body cannot get enough oxygen. Common symptoms of anemia include tiredness, weakness, and shortness of breath.

SCD also causes intense episodes of pain called pain crises. Sickle cells may block the blood flow through blood vessels to the chest, abdomen, and joints. This blockage may result in pain episodes that vary in intensity, length, and frequency. Additionally, lack of blood circulation may lead to swelling in the hands and feet.

If sickle cells get trapped in the blood vessels of the spleen, then the spleen will become enlarged as the blood builds up. This is known as splenic sequestration and can damage the spleen, which is important for protection against infections. Increasing pain on the left side, severe belly pain or swelling, fatigue, and dizziness are all indicators of splenic problems.

SCD may also cause delays to puberty because the red blood cells are unable to deliver the oxygen and nutrients needed for proper growth.

If the blood cells lead to the eyes becoming clogged, then damage to the retinas may occur. This may lead to vision problems because visual images can no longer be properly processed.

What are the complications?

Complications occur when a disease worsens, causing the individual to experience additional symptoms. Complications of SCD include:

  • Stroke: blocked blood flow to brain
  • Acute chest syndrome: blocked blood flow to lungs
  • Avascular necrosis: blocked blood flow to bones
  • Pulmonary hypertension: high blood pressure in lungs
  • Organ damage: blocked blood flow to organs
  • Splenic sequestration: sickle cells become trapped in spleen, causing it to enlarge
  • Blindness
  • Leg ulcers
  • Gallstones
  • Priapism: long-lasing erections
  • Deep vein thrombosis: blood clots in deep veins
  • Pregnancy complications: anemia

How does it impact daily life?

Since SCD is a lifelong illness, it demands certain lifestyle changes to manage its symptoms and complications. Individuals with SCD should drink lots of water and not get too hot or too cold. They should avoid high altitudes and exposure to low oxygen levels. This means they should limit flying, mountain climbing, cities at high altitudes, and extreme exercise. Additionally, good hygiene such as washing their hands is necessary to prevent infections.

How is SCD treated?

The standard treatments for SCD approved by the FDA are bone marrow and stem cell transplants. This course of action is mostly used for cases of severe SCD in children who have minimal organ damage.

Other treatments attempt to relieve pain and prevent complications. Vaccines prevent infections and visits to the eye doctors limit vision loss. Blood transfusions attempt to prevent stroke and treat anemia, while iron chelation therapy prevents excess iron buildup from transfusions. Pain reduction medication, IVs, and hospitalization are used to treat pain crises.

Can gene editing be used as a therapeutic?

As of December 2023, the FDA approved Casgevy, a treatment for SCD based on CRISPR-gene editing technology. Vertex Pharmaceuticals and CRISPR therapeutics created Casgevy and it is approved for sickle cell patients over the age of 12. This treatment is the first FDA-approved therapeutic that utilizes CRISPR/Cas9. The following steps are required for a patient to be treated with Casgevy:

  1. The patient receives blood transfusions to reduce the amount of sickle cells in their bloodstream.
  2. The patient’s stem cells are collected.
  3. The patient undergoes high-dose chemotherapy known asmyeloablative conditioning to remove blood cells in bone marrow that make the sickle cell hemoglobin.
  4. The patient’s stem cells aremodified by Casgevy to produce high levels of fetal hemoglobin (HbF), which binds to oxygen more tightly than adult hemoglobin.
  5. The modified stem cells are transplanted back into the patient.
  6. The stem cells attach and multiply within the bone marrow, preventing the number of sickle cells in the body and reducing symptoms of SCD.

While Casgevy appears to be revolutionizing treatment for SCD, its high price may prevent many patients from receiving the cure they need. Estimated to cost $2.2 million per patient, only time will tell if insurance companies are willing to cover this high up front fee. Additionally, access to treatment for SCD is a barrier in places beyond the United States. Sickle cell disease is most common in sub-Saharan Africa, where only 3 centers for bone marrow transplants exist. The expansion of care for patients with SCD calls for low-cost treatments that fit into the daily lives of patients, which will not be possible without increased investment into healthcare infrastructure and clinical trials worldwide.

– Masin Kearney