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Writer's pictureThe Rare360 Editorial Team

Understanding Sickle Cell Disease: A Deep Dive into Diagnosis, Symptoms, and Modern Therapies

Updated: Oct 23

Illustration showing the flow of blood through a blood vessel with a mixture of normal red blood cells and some sickle-shaped cells.

Sickle cell disease is a hereditary blood disorder that affects millions of people worldwide, primarily those of African, Mediterranean, Middle Eastern, and Indian ancestry. This condition causes red blood cells to become rigid and shaped like a crescent or "sickle," impairing their ability to transport oxygen effectively throughout the body. This blog article explores the causes, symptoms, complications, diagnosis, and treatment options for sickle cell disease, providing a comprehensive guide to understanding this genetic disorder.


What is Sickle Cell Disease?

Sickle cell disease is the most common inherited blood disorder, affecting the way the red blood cells function. Normally, red blood cells carry oxygen throughout the body using a protein called hemoglobin, which is located inside these cells. In people with sickle cell disease, the hemoglobin is abnormal (called Hemoglobin S or HbS), which causes the red blood cells to change shape, forming a crescent or “sickle” shape instead of the usual round, flexible form.


These sickle-shaped cells are less flexible and tend to stick together, blocking blood vessels and preventing oxygen from reaching vital organs and tissues. This can lead to serious complications such as pain, infections, and even damage to major organs. Additionally, these sickle cells die much sooner than healthy cells—often lasting only 10 to 20 days instead of the normal 90 to 120 days—causing a shortage of red blood cells, a condition known as anemia.


In the past, babies born with sickle cell disease often had shorter lifespans. However, due to recent advances in medical treatments and early diagnosis, people with this condition now have a much better chance of living into their 50s or beyond. While there are still serious risks and complications, treatments today can reduce these risks and help manage symptoms, improving the quality of life for many individuals. Despite this progress, access to effective treatments remains limited in certain parts of the world, leaving many without the care they need.


Causes of Sickle Cell Disease

Sickle cell disease is caused by a genetic mutation in the HBB gene, which provides instructions for producing a part of hemoglobin. In people with sickle cell disease, this gene is altered, leading to the production of abnormal hemoglobin, known as hemoglobin S.


Sickle cell disease is inherited in an autosomal recessive pattern. Individuals with sickle cell disease inherit two copies of this mutated gene—one from each parent. This means both parents of a child with this condition carry one copy of the mutated gene, but typically do not show symptoms themselves. If a person inherits only one sickle cell gene, they have what’s called "sickle cell trait." People with sickle cell trait are usually healthy but can still pass the sickle cell gene on to their children.


Sickle cell disease is more common in individuals whose ancestry traces back to regions where malaria was historically prevalent. In these regions, carrying one sickle cell gene provides partial protection against malaria, but inheriting two copies leads to sickle cell disease.


It is relatively rare in the United States, affecting approximately 100,000 people. In the US, it is well known to affect individuals of modern African and Mediterranean ancestry, but it can also affect those with roots in southern Europe, the Middle East, or South Asia. Here's a closer look at how the condition affects different populations in the US:

  • Approximately 1 in 13 Black babies are born with sickle cell trait, meaning they have inherited one sickle cell gene from a parent.

  • About 1 in every 365 Black babies are born with sickle cell disease, having inherited the sickle cell gene from both parents.

  • About 1 in every 16,300 Hispanic American babies are born with sickle cell disease.

  • Currently, there is insufficient data regarding the prevalence of sickle cell disease in White babies.

Globally, over 8 million people are affected by sickle cell disease, with most cases occurring in regions linked to malaria.


Symptoms of Sickle Cell Disease

Symptoms of sickle cell disease usually begin to show around 6 months of age, but they can differ from person to person and may change as time passes. Common symptoms include:

  • Anemia: This is the most common symptom. Anemia happens when the body has fewer red blood cells than normal, leading to symptoms like fatigue, dizziness, and shortness of breath. Severe anemia can make an individual feel extremely weak or exhausted.

  • Jaundice (Yellowing of the skin, eyes, and mouth): Sickle cells have a shorter lifespan than healthy red blood cells. As they die off faster than the liver can filter them out, a yellow substance called bilirubin is released, causing a yellowish tint in the skin and eyes.

  • Pain crisis (sickle crisis): Periodic episodes of intense pain, known as pain crises, occur when sickle-shaped red blood cells block blood flow to areas like the chest, abdomen, and joints. The pain can range from mild to severe and may last a few hours to several days. Some people experience only a few crises a year, while others may have multiple episodes, requiring hospitalization.

  • Swelling of Hands and Feet: Sickle cells can block blood circulation in the hands and feet, causing them to become swollen and painful.

  • Frequent Infections: Sickle cells can damage the spleen, an organ that helps protect the body from infections. This raises the risk of severe infections, especially in babies and children. Vaccinations and antibiotics are often prescribed to prevent life-threatening infections like pneumonia.

  • Delayed Growth and Puberty: A lack of healthy red blood cells can slow down growth in children and delay puberty in teenagers. This is because the body isn’t getting enough oxygen and nutrients to grow normally.


Complications of Sickle Cell Disease

  • Acute chest syndrome: This life-threatening condition happens when sickle cells block oxygen flow in the lungs. It often occurs during times of infection, fever, or dehydration. Symptoms may mimic pneumonia and include fever, chest pain, and severe coughing.

  • Splenic Sequestration (Pooling): The spleen becomes enlarged and painful when sickle cells become trapped. This can lead to a sudden drop in hemoglobin, reducing the number of red blood cells circulating in the body. If not treated quickly, this can be fatal.

  • Stroke: Sickle cells can block blood flow to the brain, leading to a stroke. A stroke can cause serious brain damage and often requires immediate medical attention. People with sickle cell disease who have had a stroke are at higher risk of experiencing another one. Approximately 11% of people with sickle cell disease have strokes by age 20, and 24% have strokes by age 45.

  • Priapism: Sickle cells can block blood flow to the penis, causing painful and prolonged erections. If left untreated, this can lead to erectile dysfunction. About 35% of all people who are assigned male at birth (AMAB) who have sickle cell disease develop priapism, or painful erections, that last four hours or more.

  • Avascular necrosis: Sickle cells can block the blood vessels that supply blood to the bones. When the bones don't get enough blood, joints may narrow and bones can die. This can happen anywhere but most often happens in the hip.

  • Pulmonary hypertension: People with sickle cell disease can develop high blood pressure in their lungs. This complication usually affects adults. Shortness of breath and fatigue are common symptoms of this condition, which can be fatal.

  • Organ damage: People with sickle cell disease are at risk for problems related to their heart, lung, kidneys and other organs. This is because blood and oxygen aren’t reaching them. SCD can lead to multi-organ failure.

  • Vision problems: Sickle cells can block tiny blood vessels that supply blood to the eyes. This blockage occurs most often in the retina of your eye. An individual affected by sickle cell disease may not have any symptoms and then suddenly have vision loss, which can lead to permanent blindness.

  • Leg ulcers: Sickle cell disease can cause painful open sores on the legs.

  • Gallstones: The breakdown of red blood cells produces a substance called bilirubin. A high level of bilirubin in the body can lead to gallstones.

  • Deep vein thrombosis: Sickled red blood cells can cause blood clots, increasing the risk of a clot lodging in a deep vein, known as deep vein thrombosis. It also increases the risk of a blood clot lodging in a lung, known as pulmonary embolism. Either can cause serious illness or even death.

  • Pregnancy complications: Sickle cell disease can increase the risk of high blood pressure and blood clots during pregnancy. It also can increase the risk of miscarriage, premature birth and low birth weight and premature babies.


Diagnosis of Sickle Cell Disease

Healthcare providers diagnose sickle cell disease through a combination of physical examinations, medical history reviews, and laboratory tests. During the diagnosis of sickle cell disease, healthcare providers begin with a thorough physical examination. They may palpate the spleen and liver to check for any enlargement or tenderness, as these organs can be affected by the disease. In addition to the physical exam, providers will assess symptoms commonly associated with sickle cell disease, such as pain in the arms, legs, or abdomen, which are hallmarks of the condition. A review of the patient's medical history is also conducted, with particular attention to any recurrent infections or health issues that might be linked to sickle cell disease.


Common Diagnostic Tests:

  • Blood Test: These tests help diagnose anemia by measuring red blood cell counts and examining their shape under a microscope. The presence of sickle-shaped red blood cells is a key indicator of sickle cell anemia. Blood tests also measure the amount of hemoglobin S, the defective form of hemoglobin responsible for the disease.

  • Genetic Testing: Genetic tests can confirm whether a person carries one or two copies of the sickle cell gene. This helps in verifying a diagnosis, especially when blood test results are inconclusive.


Additional Diagnostic Methods for Suspected Cases:

  • Prenatal Screening: Sickle cell disease can be diagnosed before birth through:

    • Amniocentesis: A sample of the amniotic fluid surrounding the baby is tested for the presence of the sickle cell gene.

    • Chorionic Villus Sampling (CVS): A sample from the placenta, which nourishes the baby, can also be analyzed to detect sickle cell disease early in pregnancy.

  • Newborn Screening: In many countries, including the United States, newborn screening for sickle cell disease is standard practice. Since 2007, all newborns in the U.S. are tested shortly after birth. These screenings also identify whether the baby carries the sickle cell trait (i.e., one copy of the hemoglobin S gene).

  • Hemoglobin Electrophoresis: Also known as High-Performance Liquid Chromatography (HPLC), this test measures and identifies different types of hemoglobin in the blood. It can accurately detect abnormal hemoglobin, including hemoglobin S, to confirm a diagnosis of sickle cell disease.

When a person is diagnosed with sickle cell disease, additional tests may be recommended to check for complications, such as organ damage or infections. If genetic testing reveals that the person carries the sickle cell gene, they may be referred to a genetic counsellor to discuss the implications of being a carrier and future family planning options.


Treatment of Sickle Cell Disease

While there isn’t a widely available cure for sickle cell disease, treatments aim to manage symptoms, prevent complications, and improve quality of life. Treatment options include:

  • Medications: Several FDA-approved medications target different aspects of the disease:

    • Hydroxyurea: Hydroxyurea, initially approved as a cancer drug, was the first medication approved for sickle cell disease in 1998. It works by reducing the sickling of red blood cells, which helps prevent pain crises and other severe symptoms of the disease. Hydroxyurea may also reduce the need for blood transfusions and hospitalizations. However, it increases the risk of infections, making careful monitoring necessary. This oral drug is safe for adults and children as young as 9 months old but should not be used during pregnancy due to potential harm to the fetus.

    • Voxelotor (Oxbryta): Voxelotor, another oral medication, was developed to prevent the sickling of red blood cells. It improves oxygen transport in the blood and reduces anemia by increasing hemoglobin levels. Approved for use in individuals aged 4 years and older, Voxelotor can enhance blood flow and improve overall patient health. Common side effects include headache, nausea, diarrhea, fatigue, rash, and fever.

    • L-glutamine: L-glutamine is approved for patients aged 5 years and older to reduce the frequency of painful vaso-occlusive crises (pain crises). It works by improving the redox balance in sickled red blood cells, which helps prevent damage and reduces the risk of complications like acute chest syndrome. Taken as a powder mixed with liquids or soft foods, L-glutamine may decrease hospitalizations, pain episodes, and the need for blood transfusions. Side effects include nausea, fatigue, chest pain, and bone or muscle pain.

    • Crizanlizumab (Adakveo): Crizanlizumab is an intravenous (IV) medication that helps prevent the adhesion of sickled red blood cells to blood vessel walls, reducing blockages that cause pain crises. Approved for patients aged 16 years and older, this monthly infusion helps lower the need for blood transfusions, reduces inflammation, and can lessen the frequency of pain episodes. Possible side effects include nausea, joint pain, back pain, and fever.

    • Additional medications:

      • Pain Relievers: For managing acute or chronic pain crises, over-the-counter or prescription pain medications may be recommended.

      • Antibiotics: To prevent infections, especially in young children with sickle cell disease, daily penicillin may be prescribed.

      • Folic Acid Supplements: Since sickle cell patients often experience anemia, folic acid supplements can help the body produce new red blood cells.

      • Blood Pressure Medications: In some cases, medications to control blood pressure may be prescribed to help reduce complications related to kidney disease.

 

  • Bone Marrow/Stem Cell Transplant

    A bone marrow or stem cell transplant is the only potential curative therapy for some individuals with sickle cell disease. This procedure involves replacing the patient's malfunctioning bone marrow with healthy blood-forming stem cells from a well-matched donor, usually a close blood relative, such as a sibling. The success of a transplant heavily relies on finding a compatible donor through Human Leukocyte Antigen (HLA) testing. HLAs are proteins that play a crucial role in the body’s immune response and are used to assess tissue compatibility between donor and recipient.

    Transplants are primarily performed on children with severe complications, such as strokes, acute chest syndrome, or frequent pain crises, as they tend to have better outcomes than adults. In children with minimal organ damage, bone marrow transplants can be up to 90% successful when the donor is an HLA-matched relative. However, despite the high success rate, the procedure carries significant risks, particularly for adults.

    Potential Complications of Transplant

    Even with careful planning, a bone marrow or stem cell transplant can lead to serious complications, including:

    • Graft-versus-host disease (GVHD): Transplanted cells attack the recipient’s organs.

    • Increased cancer risk: There is a higher likelihood of developing certain cancers later in life.

    • Infertility: The treatment may impact fertility.

    • Seizures: Neurological complications like seizures can occur.

    • Serious infections: The immune system is compromised after a transplant, raising infection risks.

    • Transplant failure: If the transplant fails, sickle cell disease may return.

    While bone marrow or stem cell transplants offer hope for a cure, the risks and benefits must be carefully weighed, particularly in adult patients, where the procedure is generally more hazardous.

 

  • Gene Therapy

    Gene therapy is a groundbreaking FDA-approved treatment for sickle cell disease that works by modifying the DNA in a person's stem cells to correct the defective gene responsible for the disease. In this process, stem cells are removed from the patient’s body, and the sickle cell gene is "edited" to restore the cells' ability to produce healthy red blood cells. These treated stem cells are then infused back into the bloodstream, where they replace the defective ones.


    Patients who successfully undergo gene editing therapy no longer exhibit symptoms of sickle cell disease. Currently, this treatment is approved for individuals aged 12 and older. However, the long-term effects of gene therapy are still being studied.

    In December 2023, the U.S. FDA approved two specific cell-based gene therapies for treating sickle cell disease in patients 12 years and older:

    • Exagamglogene autotemcel (CASGEVY™)

    • Lovotibeglogene autotemcel (LYFGENIA™)

    Both therapies are derived from the patient's own stem cells. Before treatment, the patient undergoes high-dose chemotherapy to eliminate the existing bone marrow cells, allowing the modified stem cells to replace them. This gene therapy is delivered as a single, one-time infusion.

There are several clinical trials underway aimed at discovering new treatments for sickle cell disease. If you or a loved one has been diagnosed with sickle cell disease and are seeking to explore potential treatment options, Know Rare’s team may be able to assist you in connecting with active clinical trials. These trials may provide access to innovative therapies that may be more effective at managing the condition.


Conclusion

Sickle cell disease continues to present challenges for patients and their families, but advancements in diagnosis, treatment, and gene therapy offer hope for a brighter future. While current treatments like hydroxyurea, and other medications may help manage symptoms, breakthroughs in gene therapy may pave the way toward a potential cure. These developments are especially promising for younger patients who are more likely to benefit from cutting-edge therapies.


Despite these strides, disparities in healthcare access, particularly in under-resourced regions, remain a pressing issue. Advocacy for equitable healthcare access is critical, ensuring that all individuals living with sickle cell disease receive the treatment and support they need.


Looking ahead, the scientific community’s commitment to research, innovation, and patient care continues to fuel optimism for those affected by sickle cell disease. With continued progress, we can hope for a future where sickle cell disease no longer limits the lives of millions.


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