• Disease Overview
  • Synonyms
  • Subdivisions
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Video
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Sickle Cell Disease

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Last updated: 03/14/2024
Years published: 1984, 1985, 1987, 1989, 1990, 1992, 1993, 1994, 1995 , 1996, 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2006, 2017, 2024


Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, Brazilian MD, MS, National Organization for Rare Disorders and MA Bender, MD, PhD, Department of Pediatrics, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington, for assistance in the preparation of this report.


Disease Overview

Summary

Sickle cell disease (SCD) is a rare blood disorder that is inherited in an autosomal recessive manner. It is characterized by the presence of sickle, or crescent-shaped, red blood cells (erythrocytes) in the bloodstream. These crescent-shaped cells are stiff and sticky and interact with other cells and the blood clotting system to block blood flow in the very tiny blood vessels (capillaries) of the peripheral blood system (blood vessels outside of the heart). This prevents the normal flow of nutrition and oxygen (as red blood cells are responsible for carrying oxygen throughout the body).

Common symptoms associated with SCD include excruciating bone pain, chest pain, severe infections (primarily in children), low levels of circulating red blood cells (anemia) and yellowing of the skin (jaundice). The blocked blood flow can also cause severe organ damage including stroke. SCD has several recognized forms including sickle cell anemia, sickle cell hemoglobin C disease, and sickle cell / beta-thalassemia disease.

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Synonyms

  • SCD
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Subdivisions

  • sickle cell anemia or SCD (Hb S/S)
  • sickle cell-beta-thalassemia disease syndrome or sickle beta-thalassemia, subdivided in two subtypes: Hb S/β+-thalassemia or SCD (HbS beta0 ); and Hb S/β0-thalassemia or SCD (HbS beta+)
  • sickle cell-hemoglobin C disease syndrome or SCD (Hb S/C)
  • sickle cell-hemoglobin D disease syndrome or SCD (Hb S/D)
  • sickle cell-hemoglobin E disease syndrome or SCD (Hb S/E)
  • hereditary persistence of fetal hemoglobin-sickle cell disease syndrome (or HPFH)
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Signs & Symptoms

Hemoglobin is an iron-rich protein contained in red blood cells and is responsible for carrying oxygen from the lungs to the rest of the body. In SCD, the symptoms stem from the abnormal hemoglobin in the red blood cells. The abnormal hemoglobin causes the red blood cells to be sickle-shaped which triggers a series of events leading to fragile red blood cells and blocking blood flow.

The most common signs and symptoms of SCD are associated with low red blood cells (anemia) and pain. The most common symptom of anemia is feeling tired and weak (fatigue). Sickle cell pain episodes can occur suddenly and is typically in bones and the abdomen, but can occur almost anywhere. The pain can last for days to over a week (acute) or continue long-term (chronic). Damage can occur to most parts of the body including the brain, lung, kidneys, and joints. SCD can cause yellow eyes (jaundice) from the breakdown of blood. Signs in infants can include swollen and painful hands and/or feet (dactylitis), irritability, crying, and severe infections.

In patients with SCD, the spleen can become enlarged (splenomegaly) as it traps red blood cells that should be in the bloodstream. The spleen functions to filter out abnormal red blood cells and fights some infections such as the bacteria that cause strep throat. Damage to the spleen leads to decreased ability to fight some typically mild infections that can become life-threatening in SCD.

Acute chest syndrome can occur if an infection or sickled cells damages the lungs. This is a life-threatening complication of SCD. Sometimes people can’t tell they have it but other times people can have chest pain, difficulty breathing or fever. Additional complications of SCD include stroke, which can occur in children as young as 2 years. Boys and men with sickle cell disease may experience painful, prolonged erections (priapism) at any age.

The signs and symptoms of SCD vary from patient to patient, and some patients have more mild symptoms while others may have more severe symptoms requiring hospitalization. SCD is present at birth; however, most infants do not show any signs until four months of age and many do not show signs until several years of age. The symptoms typically begin in the first three years of life. Sometimes the first suggestion of SCD is a painful swelling of an infant’s hands or feet (dactylitis). The extreme pain episodes are often triggered by something such as getting cold, becoming dehydrated, infection, over doing it, or trauma. Children with SCD may grow slowly and reach puberty later.

As people with SCD age, other additional complications become more common. Pulmonary hypertension can develop due to damage to the small blood vessels and air sacs in the lungs. This can cause decreased ability to exercise, shortness of breath and tiredness. Leg sores that are often hard to heal can occur; damage to the retina can occur causing eye problems. Damage to the joints (avascular necrosis) and the loss of bone may cause pain in the joints when walking, standing and/or lifting. Kidney damage can occur and gallstones are often present.

There are many forms of SCD. The most common severe form is S/S which some call sickle cell anemia. Some forms, like sickle beta-zero thalassemia are just as severe as the S/S form. Sickle beta-plus thalassemia and sickle cell hemoglobin C disease are usually less severe. Diagnosing exactly what form of SCD someone has is important and there is a lot of confusion about the different forms.

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Causes

Sickle cell disease is caused by changes (variants) in both copies of the hemoglobin beta (HBB) gene.

The HBB gene provides instructions for making a protein called beta-globin. Beta-globin is a component (subunit) of a larger protein called hemoglobin, found inside red blood cells. In adults, hemoglobin consists of four protein subunits: typically, two subunits of beta-globin and two subunits of a protein called alpha-globin, which is produced from another gene called HBA. Each of these protein subunits is attached to an iron-containing molecule called heme. The iron in the center of each heme can bind to an oxygen molecule.

Hemoglobin inside red blood cells binds to oxygen molecules in the lungs. These cells then travel through the bloodstream and carry oxygen to tissues throughout the body. Hemoglobin is the main substance of red blood cells. It helps red blood cells carry oxygen from the air in the lungs to all parts of the body. Normal red blood cells contain hemoglobin A. Normal red blood cells that contain hemoglobin A are soft and round and can pass through small blood tubes (vessels). Normally, red blood cells live about 120 days before new ones replace them.

There are several forms of sickle cell disease. The most common form of sickle cell disease is sickle cell anemia (HbSS disease). This form is caused by a particular variant in the HBB gene that results in the production of an abnormal version of beta-globin called hemoglobin S (HbS). People who have sickle cell anemia inherit two disease-causing hemoglobin gene variants for hemoglobin S from each parent, so hemoglobin S replaces both beta-globin subunits in hemoglobin.

The variant that causes hemoglobin S changes a single component (amino acid) of the beta-globin protein. Specifically, the amino acid glutamic acid is replaced by the amino acid valine at position 6 of beta-globin, written as Glu6Val or E6V. This change results in abnormal subunits of hemoglobin S that stick together and form long, rigid molecules that bend red blood cells into a sickle (half-moon) shape.

Sickle cells die too soon (they only live about 16 days), which can cause a shortage of red blood cells (anemia). When sickle cells block small blood vessels, less blood can reach that part of the body. Parts of the body that do not receive normal blood flow eventually become damaged and this is what causes the complications of sickle cell anemia.

Other variants of the HBB gene can cause other abnormalities in beta-globin, resulting in other types of sickle cell disease. These abnormal forms of beta-globin are often designated by letters or sometimes by a name. They occur when a person inherits a hemoglobin S gene from one parent and a disease-causing variant in a hemoglobin gene, such as beta (β) thalassemia, hemoglobin C, hemoglobin D, or hemoglobin E, from the other parent. In these other types of sickle cell disease, only one subunit of beta-globin is replaced with hemoglobin S. The other subunit of beta-globin is replaced with a different gene variant, such as beta thalassemia, hemoglobin C, or hemoglobin D or E.

In hemoglobin SC (HbSC) disease, the beta-globin subunits are replaced by hemoglobin S and hemoglobin C. Hemoglobin C is produced when the amino acid lysine replaces the amino acid glutamic acid at position 6 in beta-globin (written Glu6Lys or E6K). The severity of hemoglobin SC disease is variable but can be as serious as sickle cell anemia.

Hemoglobin E (HbE) is produced when the amino acid glutamic acid is replaced by the amino acid lysine at position 26 of beta-globin (written Glu26Lys or E26K). In some people, the hemoglobin E variant is present with hemoglobin S. these people may have more severe signs and symptoms associated with sickle cell anemia, such as episodes of pain, anemia and abnormal spleen function.

Another condition, known as sickle hemoglobin-beta thalassemia, occurs when the variants that cause hemoglobin S and beta thalassemia (mentioned above) occur together. Variants that combine sickle cell anemia with beta-zero (β0) thalassemia cause severe disease, while sickle cell disease combined with beta-plus (β+) thalassemia is generally milder.

People who inherit only one copy (allele) of an altered HBB gene are said to have “sickle cell trait” or to be “carriers” of the sickle cell trait. They have one allele with a normal HBB gene (HbA) and one allele with HBB gene variant (HbS or sickle gene). The HbA allele produces normal hemoglobin, HbA and the HbS allele produces an abnormal hemoglobin, HbS, that sticks together and causes sickle red blood cells. The HbA and HbS alleles are said to be “codominant” as both are expressed. This means that people with sickle cell trait will have some red blood cells that have a normal shape and some red blood cells that have a sickle shape.

Most people with sickle cell trait do not have any symptoms of sickle cell disease, although, in rare cases, might develop complications of sickle cell disease, such as pain crises, especially under certain conditions such as increased pressure in the atmosphere (for example, while scuba diving), low oxygen levels in the air (for example, when mountain climbing, exercising extremely hard in military boot camp, or training for an athletic competition), dehydration, high altitudes (such as when flying, mountain climbing, or visiting a city at a high altitude).

Of note, the sickle cell trait protects against severe and uncomplicated malaria. This means that if a mosquito carrying the malaria germ bites someone with sickle cell trait, the person isn’t as likely to get as sick as other people. That’s because people with sickle cell trait have red blood cells that make it hard for the malaria germ to grow. Malaria is a serious disease caused by a parasite that infects a certain type of mosquito. It is not common in United States, but it is endemic in many countries.

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Affected populations

The frequency of SCD varies from country to country. SCD affects 0.6 percent of the African American population in the United States (approximately 100,000 cases in the United States). It is also common in people of Hispanic decent, from India, Central America and the Arabian Peninsula, but can occur in people of any background. SCD affects approximately one in every 300 – 500 African American newborns. The sickle cell trait is present in approximately 40 percent of the general population in some areas of Africa. The incidence of sickle cell trait in Americans of African descent is 9 percent.

Variants in the HBB gene are common in people from African, Mediterranean, Middle Eastern, and Indian ancestry and in people from the Caribbean and parts of Central and South America, but can be found in people of any ethnicity.

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Diagnosis

Newborn babies in the U.S. (all 50 states and the District of Columbia) are screened for sickle cell status (SCD or SCT) 24-48 hours after birth as part of the newborn screening program. The screening test is done using electrophoresis and/or high-pressure liquid chromatography. A positive newborn screening test means that a baby is likely to have SCD or SCT, but additional testing is needed to confirm the diagnosis. Molecular genetic testing for variants in the HBB gene is also available.

The following pamphlet from the Centers for Disease Control and Prevention (CDC) has additional information: Get Screened to Know Your Sickle Cell Status.

In 2013, the Association of Public Health Laboratories’ (APHL’s) Newborn Screening and Genetics in Public Health Program and the Centers for Disease Control and Prevention’s (CDC’s) Division of Blood Disorders began working together on the Newborn Screening and Genetics – Hemoglobinopathies Project to help prevent and lower complications related to hemoglobinopathies such as sickle cell disease (SCD) . Hemoglobinopathies is the medical term for a group of blood disorders and diseases affecting red blood cells. The CDC offers detailed information about sickle cell disease, including diagnosis.

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Standard Therapies

Treatment
Management of SCD is focused on preventing and treating pain episodes and other complications. Prevention strategies include lifestyle behaviors, medical screening and interventions to prevent SCD complications. Patient and family education, medicines such as hydroxycarbamide, avoiding triggers, early intervention and testing to pick up developing complications early so they can be treated before they are severe can significantly improve outcomes.

While very few patients with SCD have the opportunity to be cured, early referral of newborns to specialty centers can provide education and resources that help control symptoms and dramatically improve quality of life for patients. People with SCD should have regular medical checkups where education on preventing complications has a tremendous benefit on health. Teaching families about how to carefully monitor children for fevers while at home, giving low dose penicillin and immunizations and assuring families have the information and ability to reach a hospital when ill dramatically decreases severe infections and death. Many simple lifestyle activities can be done to support health and minimize pain and other complications. These include remaining hydrated, not getting too hot or cold, getting exercise, deep breathing, not getting fatigued and avoiding trauma.

It is important to try to avoid sickle cell pain. Once pain occurs, it is important to use many approaches to treat the severe pain in SCD in addition to medications. Reversing triggers of pain is key, thus hydration, remaining warm, walking around and deep breathing are very important. Distraction can be a huge help, as are approaches such as massage, acupuncture and hypnosis. Pain-relieving medications such as non-steroidal anti-inflammatory agents and opiate analgesics may be administered during painful episodes.

Blood transfusions can be used for many reasons such as very severe anemia, preparing for surgery and to reduce the risk of, or treat stroke. In some people, surgery may be necessary because of damage to specific organs such as gall bladder surgery (cholecystectomy) to remove gallstones.

Stem cell transplants can provide a cure for patients, but the chance of success and potential risks vary and depend on many factors.

Hydroxycarbamide (hydroxyurea) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of SCD and is recommended for most patients with the S/S and sickle beta-zero thalassemia types of SCD. It should be offered to children with these types of SCD by 9 months of age. Hydroxyurea helps stimulate the body to make fetal hemoglobin, the type of hemoglobin that newborns have and lowers white blood cells that can contribute to slowing blood flow. As a result, hydroxycarbamide can decrease pain, improve anemia, decrease hospitalizations and lung problems and increase lifespan.

Folic acid is used to ensure the body can make enough red blood cells.

In 2017, the FDA approved L-glutamine (Endari) for patients aged five years and older with SCD to reduce severe complications associated with this condition.

In 2019, the FDA approve two drugs for the treatment of SCD. Voxelotor (Oxbryta) was approved to treat SCD in adults and pediatric patients 12 years of age and older and crizanlizumab-tmca (Adakveo) was approved as a treatment to reduce the frequency of vaso-occlusive crisis in SCD patients aged 16 years and older.

In 2023, A cell-based gene therapy called lovotibeglogene autotemcel (Lyfgenia) was approved by the FDA to treat patients 12 years of age or older with SCD who have had recurrent vaso-occlusive crises.

In 2023, A cell-based gene therapy called exagamglogene autotemcel (Casgevy) was approved by the FDA to treat patients 12 years of age and older with SCD who have had recurrent vaso-occlusive crises. Casgevy is the first FDA-approved genome editing therapy.

Genetic counseling is recommended for affected individuals and their families.

The CDC has a page with SCD facts that includes updated information about treatment.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Kuriri FA. Hope on the horizon: new and future therapies for sickle cell disease. J Clin Med. 2023 Sep 1;12(17):5692 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10488840/

Ngou CM, Bayibéki AN, Abate L, et al. Influence of the sickle cell trait on Plasmodium falciparum infectivity from naturally infected gametocyte carriers. BMC Infect Dis. 2023;23(1):317. Published 2023 May 10. doi:10.1186/s12879-023-08134-x

Xu JZ, Thein SL. The carrier state for sickle cell disease is not completely harmless. Haematologica. 2019 Jun;104(6):1106-1111.

INTERNET
Bender MA, Carlberg K. Sickle Cell Disease. 2003 Sep 15 [Updated 2023 Dec 28]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1377/ Accessed March 13, 2024.

Sickle Cell Disease. MedlinePlus. July 1, 2020. Available at: https://ghr.nlm.nih.gov/condition/sickle-cell-disease Accessed March 13, 2024.

Sickle Cell Anemia. National Heart, Lung, and Blood Institute. Aug 30, 2023. Available at: https://www.nhlbi.nih.gov/health/health-topics/topics/sca Accessed March 13, 2024.

Sickle Cell Disease (SCD). Centers for Disease Control and Prevention (CDC). Oct 3, 2023. Available at: https://www.cdc.gov/ncbddd/sicklecell/index.html Accessed March 13, 2024.

Sickle Cell Disease. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:603903; 02/10/2023
Available at https://omim.org/entry/603903 Accessed March 13, 2024.

What is Sickle Cell Trait? Centers for Disease Control and Prevention (CDC). 2023. https://www.cdc.gov/ncbddd/sicklecell/traits.html Accessed March 13, 2024.

Malaria Disease Basics. Centers for Disease Control and Prevention (CDC). February 14, 2024. https://www.cdc.gov/malaria/about/ Accessed March 13, 2024.

What’s the Connection Between Sickle Cell Trait and Malaria? Nemours Children Health. July, 2023. https://kidshealth.org/en/teens/sickle-cell-trait-malaria.html Accessed March 13, 2024.

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Programs & Resources

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NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations


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