Sicklepedia: Online Sickle Cell Encyclopedia

Sickle Cell Disorders

Sickle cell disorders are a group of inherited blood disorders that are caused by a mutation, or change in DNA. This change alters the way red blood cells function in individuals with the disorder. Sickle cell disorders are genetic, meaning they are passed down from parents to their children.

Normally, red blood cells are round and flexible and can travel easily through blood vessels. However, in those with sickle cell disease, each time red blood cells release oxygen to tissues and organs, they transform into fragile, sticky, crescent (or sickle) shaped red blood cells called sickle cells. This transformation weakens sickle cells over time and they break down at a faster rate (called hemolysis), which results in anemia and other complications.

The changes in shape and stickiness also make it difficult for sickle cells to move freely through small blood vessels. This can slow down blood flow or even cause blockage to the tissues they supply with oxygen. This event is called vaso-occlusion. The blockage and lack of oxygen cause tissue damage and inflammation which is the cause of painful vaso-occlusive events (pain crises) in sickle cell disease.

Typical blood flow vs. vaso-occlusion in blood vessels

Blood flows through the entire body; therefore, any organ or tissue can be affected. When blood flow is reduced, oxygen is also reduced in the affected body parts and organs, which causes injury and even cell death. As a result, this causes damage to body parts that build up as time goes on.

These events take place inside the body every second of every day, even if pain is not present. Outcomes of the disorder include extreme pain, damage to organs, and several other complications.

Sickle Cell Disorders

White blood cells, normal red blood cells, and sickled red blood cells; Image Source: OSF Healthcare

Cause

Genetic changes

Specialty

Hematology

Most Common Symptoms

Pain, fatigue, anemia, dactylitis, fever, infections

Important Dates

1910: First discovery in western medicine

1949: Sickle cell disease becomes known as a molecular disease

2006: The World Health Organization recognizes sickle cell disease as a global health problem

2008: The United Nations creates a resolution recognizing sickle cell disease as a public health problem and creates June 19 as World Sickle Cell Day

2009: The first celebrated World Sickle Cell Day on June 19, 2009

Genetic Inheritance

Genes carry the information that determines traits, like the color of your eyes, how quickly your hair grows, how tall you are, and more. Everything about you is determined by genes that are passed down from parents to each child. Each parent contributes one copy of a gene, so you receive two copies of genes.

Hemoglobin (pronounced heem-oh-glow-bin) is the protein in red blood cells (RBCs) that carries oxygen from the lungs to the body and carries carbon dioxide from the body to the lungs to be breathed out.

Since sickle cell disease is a disorder that is inherited from your parents, you also receive two copies of the hemoglobin gene – one copy of the hemoglobin gene from each parent. The two copies form your hemoglobin genotype and determine whether your red blood cells will sickle and how often.

 

Inheriting Sickle Cell

Unaffected hemoglobin is labeled with the letter A. When there is a gene mutation, or variant, in the hemoglobin gene, like in sickle cell disorders, hemoglobin acts slightly differently (their own change in shape changes the shape of red blood cells). The sickle cell gene variant is labeled ‘S’. You receive a copy of each gene from your biological mother and one copy from your biological father; therefore, your genes are labeled with two letters, which is called your genotype. Here are some examples:

  • AA means a person is unaffected by sickle cell disease. They inherited two nonmutated hemoglobin genes, one from each parent.
  • AS means a person has one nonmutated gene and one sickle gene. This is known as sickle cell trait.
  • SS means a person has two sickle genes, one from each parent. This is known as sickle cell anemia.
  • SC, SDLos Angeles, SOArab, Sβ+(beta-plus)-thalassemia and Sβ0(beta-zero)-thalassemia means a person has one sickle gene and another hemoglobin mutation. These are generally known as sickle cell disease, although they may have another associated name.

You will often see the two-letter genes with “Hb” in front of the two letters. For example, HbAS is sickle cell trait.

These illustrations help explain how genetics works when determining sickle cell inheritance.

  • If both parents have HbSS, there is a 100% chance that each child will have HbSS
  • If one parent has HbSS and the other parent has HbAA, there is a 100% chance that each child will have HbAS
  • If one parent has HbSS and the other parent has HbAS, there is a 50% chance of having a child with HbAS and a 50% chance of a child with HbSS
  • If each parent has HbAS, the inheritance patterns will vary. With each pregnancy, three outcomes could occur:
    • The child has a 25% chance of having HbSS
    • The child has a 50% chance of having HbAS
    • The child has a 25% chance of having HbAA

Types of Sickle Cell Disease

There are many types of sickle cell disease. Any hemoglobin gene mutation (like hemoglobin C and β0/β+ thalassemia) paired with the sickle gene “S” is usually generally named sickle cell disease. They can also have another name like sickle SC disease or hemoglobin SC disease for HbSC; or Sβ0/β+ (beta-zero/beta+plus) thalassemia or sickle β0/β+ thalassemia disease for HbS β0/β+. Other rare types of sickle cell disease include sickle SD disease, sickle SE disease, and sickle SO disease. There are hundreds of hemoglobin mutations, which means new, but rare forms of sickle cell disease continue to be discovered.

The most common types of sickle cell disease are sickle cell anemia (HbSS), sickle SC disease (HbSC), sickle beta-plus thalassemia (Hb Sβ+-Thal), and sickle beta-zero thalassemia (Hb Sβ0-Thal).

Who Is Affected

Global Presence

Sickle cell disease and sickle cell trait affects millions of people globally and is particularly common amongst those with ancestry from Sub-Saharan Africa.

 Sickle cell disorders also more common in:

  • Hispanics from Central, South America, and the Caribbean
  • People of Middle Eastern descent (Saudi Arabia, Bahrain and Oman)
  • People of Mediterranean descent (Turkey, Greece, and Italy)
  • People of Southeast Asian descent (India)

About 5% of the world’s population carries a hemoglobin mutation gene—most of them being the sickle gene mutation and thalassemia gene mutation. There are twice as many babies born with sickle cell anemia (SS) than all of the major thalassemia types combined. These conditions are common in regions that have widespread malaria because the heterozygous sickle mutation (e.g., HbAS and HbSC) provide protection against malaria in some cases. Anemia, a symptom of sickle cell disease, is usually attributed to malaria in Sub-Saharan Africa.

United States Demographics

In the United States, the CDC estimated that:

  • SCD affects approximately 100,000 Americans.
  • About 1 in 13 Black or African American babies is born with sickle cell trait (SCT).
  • SCD occurs in about 1 out of every 365 Black or African American births.
  • SCD occurs in about 1 out of every 16,300 Hispanic-American births.
  • SCD occurs in about 1 out of every 100,000 Caucasian births.

History​

It is hypothesized that the sickle gene has been present in Africa for as long as 7,000 years. Although sickle cell disease was widely known in Africa, it was not discovered in Western medicine until 1910.

Walter Clement Noel was the first person described with sickle cell disease. Noel was a dental student from Grenada, who studied in Chicago. When experiencing a pain episode, Noel sought out medical care at a neighborhood hospital. Noel was assigned to Dr. Ernest Irons who was a medical resident of a well-known cardiologist, Dr. James Herrick.

When Dr. Irons looked at Noel’s blood under a microscope, he saw red blood cells shaped like a ‘sickle’ as medical literature describes. Dr. Herrick later published the first paper entitled, “Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.” Irons continued to care for Noel until he returned to Grenada, where he died in May 1916 at the age of 32 years from acute chest syndrome.

In 1949, Linus Pauling and his collaborators published a study in the journal Science entitled “Sickle Cell Anemia, a Molecular Disease.”

In 1956, Dr. Vernon Ingram and Dr. J.A. Hunt showed that a mutation replacing one amino acid with another was the main cause for the abnormal hemoglobin and changed shape of red blood cells in sickle cell disease.

In 1983, the first successful cure for sickle cell disease was reported when a bone marrow transplantation meant to cure a child with acute leukemia also cured her sickle cell disease.

Sickle Cell Date Observances

Thanks to the significant early efforts of Madame Edwidge Ebakisse Badassou from the Democratic Republic of Congo and Madame Antoinette Sassou N’Guesso from the Democratic Republic of Congo, and Madame Viviane Wade from Senegal, sickle cell disease is received greater awareness and is recognized by the World Health Organization as a public health problem that requires research, awareness, and annual recognition.

Today, we observe Sickle Cell Disease and those affected by the disease annually.

Date/Month of ObservanceObservance Name
June 19World Sickle Cell Day
JulyUK National Sickle Cell Awareness Month
SeptemberU.S. National Sickle Cell Awareness Month

Complications

Sickle Cell Disease

Signs and symptoms of sickle cell disease are different from person to person and can range from mild to severe. There are many factors that impact how severe sickle cell disease may be—even siblings may not have the same degree of severity.

Sickle cell symptoms start around one year of age; though, with severe sickle cell disease, symptoms can start as early as four to six months of age. One of the first signs a baby has sickle cell disease, other than screening, is dactylitis, which is the swelling of their hands and feet. In countries where there is no screening, dactylitis, severe infections, and anemia may help diagnose a newborn or individual with sickle cell disease. However, without the necessary early screening, most young children die before the age of three and many do not get a diagnosis until school age or even early adolescence, particularly if they have SC disease.

Many of the complications found in sickle cell disease result from hemolysis, which is the rapid breakdown of red blood cells. Other complications of sickle cell disease result from anemia and the stickiness of red blood cells that blocks blood flow. Complications can be acute, which typically develop suddenly, or chronic, which develop over time.

Type of complicationsExamples
Acute
  • Pain crises (vaso-occlusive episodes)
  • Infections
  • Acute Chest Syndrome
  • Stroke
  • Splenic sequestration
  • Severe anemia caused by Parvovirus B19
  • Priapism
  • Dactylitis (Hand-Foot Syndrome in infants)
Chronic
  • Anemia
  • Obstructive lung disease
  • Restrictive lung disease
  • Pulmonary hypertension
  • Avascular necrosis
  • Leg ulcers
  • Eye complications (retinopathy)
  • Chronic kidney disease
  • Heart disease (frequently caused by iron overload)
  • Liver disease (frequently caused by iron overload)
  • Iron overload from blood transfusions
  • Gallstones
  • Silent infarcts
  • Cognitive dysfunction

Sickle Cell Trait

Under extreme conditions, like being at a high altitude with reduced atmospheric pressure, oxygen levels, and oxygen pressure in the air, red blood cells can sickle in those with sickle cell trait and lead to medical complications. Additionally, chronic kidney disease and a very rare form of kidney cancer (renal medullary carcinoma) are also associated with sickle cell trait.

​Diagnostic Testing

During Pregnancy

Testing for sickle cell can be performed during pregnancy. A prenatal test can be conducted to find out if the fetus has sickle cell disease or sickle cell trait by collecting a sample of the amniotic fluid, the fluid around the baby. Chorionic villus sampling, a DNA test, is an additional way to test the baby’s sickle cell genetic status. Additionally, there is also ongoing research to test maternal blood for fetal DNA.

Newborn Screening

Newborn screening consists of a heel-prick blood sample that is then analyzed for abnormal hemoglobin. This test can identify both sickle cell disease and sickle cell trait. Universal newborn screening for sickle cell is required in every state in the United States. In the European Union, not all countries screen for sickle cell disease. In sub-Saharan Africa, there is very little screening.

Blood Test

For children and adults who are unsure if they have the sickle cell gene or any abnormal hemoglobin, they can find out with a simple blood test, provided by a healthcare provider. A hemoglobin electrophoresis test can determine if an abnormal hemoglobin gene is present, however, if a rare abnormal hemoglobin gene is detected, additional tests may be needed to confirm genetic status.

Treatments

Treatment options for sickle cell disease vary based on available resources and the associated complications. Below are some commonly recommended preventative measures and treatments for sickle cell disease complications.

Patients are highly advised to consult with their primary care provider or hematologist to ensure which treatment option, preventative option, and clinical studies are right for them.

Treatment OptionsTreatment NamePurpose/Description
PreventativeFolate/Folic Acid

 

This B vitamin is important for those with sickle cell disease because it targets anemia by working to make new red blood cells.
AntibioticsAntibiotics destroy bacteria that enter the body and further prevent potential complications that result from infections.

Babies diagnosed with SCD should begin taking penicillin as early as two months of age. While penicillin does not prevent infections alone, it prolongs the initial infectious stage that creates a fever, which gives time for the parent/caregiver to seek medical attention for proper diagnosis and treatment.

VaccinationVaccines also prevent infections or help to reduce the possibility of severe complications due to an infection. The two important vaccines to note are for Haemophilus influenzae (Hib vaccine) and Streptococcus pneumoniae (Pneumococcal vaccine).

Be sure to stay up to date with your vaccinations!

Blood TransfusionsSimple Blood Transfusion: a simple blood transfusion adds healthy blood to the body to decrease the percent of sickle cells.

Chronic Blood Transfusion: transfusions that are scheduled every two to four weeks. This therapy is usually for those with sickle cell disease that have a high risk of stroke or have had other life-threatening complications of sickle cell disease.

Exchange transfusion: the patient’s blood is removed and replaced with healthy, normal donor red blood cells. This can be done manually by a nurse or with a machine that performs an automated red cell exchange.

Pain ManagementNSAIDsNSAIDs, or non-steroidal anti-inflammatory drugs relieve pain and reduce inflammation that can also create pain in the body. They are available over the counter.

Examples: Motrin/ ibuprofen, Tylenol/acetaminophen

OpioidsOpioids are a class of drugs used to reduce or relieve pain. They are only available by prescription.

Examples: Dilaudid/hydromorphone, OxyContin/oxycodone

Alternative pain managementHeat therapy, meditation, visualization, distraction, transcutaneous electrical nerve stimulation, cannabis
FDA-Approved PharmaceuticalsHydroxyureaHydroxyurea, or hydrea, boosts the production of fetal hemoglobin, which prevents the formation of sickled cells. Hydroxyurea was FDA approved in 1998 and is a recommended treatment option for sickle cell disease.

 

The FDA approved hydroxyurea for children as young as 2 years in 2017. Some centers that start hydroxyurea earlier than two years.

L-glutamineL-glutamine helps to manage and prevent damage in red blood cells and works to reduce the number of sickle cell crises in adults and children older than age five. L-glutamine was FDA approved in 2017.
Adakveo (crizanlizumab-tmca)Adakveo is a long-term, IV infusion treatment used to reduce the frequency of pain vaso-occlusive crises in adults and pediatric patients ages 16 and older. Adakveo was FDA approved in 2019.
Oxbryta (Voxelotor)Oxbryta prevents red blood cells from transforming into sickled red blood cells because it holds some of the hemoglobin in their oxygenated position, which prevents sickling in those with HbSS particularly. This decreases hemolysis and anemia and increases oxygen delivery to the body. Oxbryta was recently FDA approved in 2019 for ages 12 and older.
CurativeBone Marrow/Stem Cell TransplantThis procedure is currently the only known cure for sickle cell disease. An HLA-matched donor, usually a sibling, is required. However, there are ongoing studies in adults to use a relative who is a “half” match, like a parent, for the stem cells.
Gene Therapy

Resources

Below are a few digital information resources for those living with sickle cell disease and their loved ones.