What are the other Names for this Condition? (Also known as/Synonyms)

• Drepanocytosis
• SCD (Sickle Cell Disease)
• Sickling Cell Disorder (SCD)

What is Sickle Cell Disease? (Definition/Background Information)

• Sickle Cell Disease (SCD) may be described as a group of inherited disorders characterized by the presence of sickle-shaped red blood cells (in blood) instead of the normally disc-shaped cells. The disease occurs worldwide, with the most significant prevalence being observed in Africa
• Sickle Cell Disease is caused by a mutation(s) in the HBB gene, which codes for beta subunits of the globin protein. For SCD to occur, an individual must possess both copies of the HBB gene in the defective form (one defective gene from each parent)
• The mutations can cause abnormalities in one or both subunits of beta globins, leading to different conformations. The two mutated subunits can occur in various combinations, making Sickle Cell Disease a group of disorders
• In individuals with Sickle Cell Disease, an abnormal form of hemoglobin known as hemoglobin S is generated, which causes the red blood cells (RBCs) to become sickle-shaped. The disc-shaped (normal) RBCs in unaffected individuals have a lifespan of about four months. Contrarily, in those with Sickle Cell Disease, the sickle-shaped RBCs live to approximately 20 days
• The sickle cells can get trapped in the spleen, and in combination with their shorter lifespan, it can result in enlarged spleen and the development of chronic anemia, which is a lifelong condition
• Apart from the above, episodes of sickle cell crisis and susceptibility to infections are some known signs and symptoms of Sickle Cell Disease. Since the sickle-shaped cells can aggregate in the blood vessels, it can result in damage to many organs, including the heart, lungs, kidney, and brain, leading to severe complications
• Sickle Cell Disease is treated with prophylactic medication to prevent infections and sickle cell crises. With newborn screening and access to proper healthcare, the lifespan of affected individuals with SCD has been increasing steadily

Who gets Sickle Cell Disease? (Age and Sex Distribution)

• Sickle Cell Disease is an inherited blood disorder that is common in Northern Mediterranean countries, North, Central, and South America, the Middle East, and India
• Individuals from endemic malarial regions such as Africa, the Mediterranean region, the Indian subcontinent, and the Saudi Arabian Peninsula are more likely to be carriers of the condition
• The disease is present at birth, but infants do not show signs and symptoms until after 4 months of age
• Both males and females are affected, and no gender preference is noted

In the United States, Sickle Cell Disease is the most common inherited blood disorder, affecting 70,000-80,000 Americans. The birth incidence is high amongst African Americans (1 in 375 babies) and Hispanics (1 in 1000-1400 babies). It is estimated that 8-10% of African Americans carry one defective copy of the gene.

What are the Risk Factors for Sickle Cell Disease? (Predisposing Factors)

• Sickle Cell Disease is an inherited genetic disorder. Therefore, having a family history of the disease is a major risk factor for the condition

It is important to note that having a risk factor does not mean one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Sickle Cell Disease? (Etiology)

Sickle Cell Disease (SCD) is caused by a mutation(s) in the HBB gene. It is inherited in an autosomal recessive manner.

• Hemoglobin is the iron-containing oxygen transport protein in the red blood cells. It contains two components, namely heme and globin. There are two alpha and two beta subunits in each hemoglobin protein molecule. Under normal circumstances, the alpha- and beta-globins assemble with the heme to form hemoglobin, which gives rise to disc-shaped red blood cells
• However, a mutation in the HBB gene can cause one or both beta-globin subunits to be malformed. The different mutated forms of beta-globin subunits may be:
  • Hemoglobin S
  • Hemoglobin C
  • Hemoglobin beta thalassemia
  • Hemoglobin D
  • Hemoglobin E
• The mutation(s) in the HBB gene can give rise to a combination of abnormal subunits, causing different forms of Sickle Cell Disease. These may include:
  • Hemoglobin SS, which causes sickle cell anemia, the most common form of Sickle Cell Disease
  • Hemoglobin SC, also a common form of SCD
  • Hemoglobin S-beta thalassemia, another common form of SCD
  • Hemoglobin SD
  • Hemoglobin SE
• When only one copy of the gene is mutated, and the other copy is normal, the resultant condition is known as sickle cell trait (SCT), a different condition from SCD
• The abnormal hemoglobin causes red blood cells (RBC) to lose their elasticity and become rigid, which is the main cause of Sickle Cell Disease. These cells tend to block small blood vessels, resulting in tissue injury
• Chronic anemia is caused when:
  • The abnormally shaped RBCs get trapped in the spleen, resulting in an enlarged spleen 
  • And the shorter lifespan of sickle-shaped RBCs in comparison to normal RBCs (20 days instead of 120 days)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Sickle Cell Disease?

The signs and symptoms of Sickle Cell Disease (SCD) may vary among affected individuals in type and severity and may include the following:

• Low hemoglobin count in blood
• An episode of “sickle cell crisis” that is associated with severe pain
  • These are periods of pain caused by occlusion of small blood vessels, resulting in tissue necrosis
  • Sickle cell crisis can occur in response to a stressful situation, changes in altitude, fever, or dehydration
  • The pain can occur in the abdomen, bones, joints, and chest
  • This kind of pain episode can last hours, a few days (4-6), or for up to weeks
  • An individual can have as many as 12 episodes a year
• Enlarged spleen (splenomegaly) due to entrapped RBCs in spleen. This is known as “splenic sequestration crisis” in SCD
• Severe anemia due to splenic sequestration crisis
• Frequent infections
• Mild jaundice causing a yellowing of the skin and whites of the eyes
• Swelling of the hands and feet, which can be painful: Hand-foot syndrome (dactylitis) is a condition that results in severe pain affecting the hands and feet. Often, dactylitis is the first symptom of SCD in babies
• Blockage of blood vessels and bleeding in the retina, causing vision impairment
• Headaches
• Loss of balance
• Weakness in one limb or one side of the body
• Confusion
• Delay in achieving developmental milestones in children
• Delayed puberty
• Priapism or persistent painful penile erection
• Joint and skeletal issues; arthritis

How is Sickle Cell Disease Diagnosed?

The diagnosis of Sickle Cell Disease is done based on the following tests and exams:

• A thorough physical examination and assessment of the presenting signs and symptoms, if any
• An evaluation of one’s family medical history
• Blood tests, to:
  • Obtain complete blood count (CBC)
  • A blood smear to check abnormalities in blood cells
  • Hemoglobin electrophoresis study to check for hemoglobin S (in the United States, newborn screening for sickle hemoglobin is performed routinely)
  • Sickle solubility test, where blood cells are lysed open to check for solubility. Hemoglobin S, a characteristic of severe Sickle Cell Disease, does not dissolve in blood plasma and remains cloudy (precipitates in plasma)
  • Serum iron level studies
• High-performance liquid chromatography (HPLC)
• Liver function tests
• Renal function tests
• Prenatal molecular genetic testing of fetal cells to check for HBB gene mutation (or sickle cell gene mutation) in the amniotic fluid

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Sickle Cell Disease?

The potential complications of Sickle Cell Disease include:

• Sickle cell anemia vaso-occlusive crisis characterized by a throbbing pain in the lower back, leg, hip, abdomen, or chest. This sickle cell crisis is triggered by a variety of situations, including infections, change in environment temperature, poor hydration status, stress, and change in altitude (such as going up the mountains)
• Severe anemia, which can result in symptoms such as extreme fatigue, pale skin, shortness of breath, and dizziness
• Formation of gallstones
• Acute chest syndrome due to low oxygen in the lungs can cause fever, cough, wheezing, and chest pain. This is also known as sickle chest syndrome
• Pneumonia
• Leg ulcers 
• Fat embolism, in which fat globules block the blood vessels 
• Bone marrow infarction, or necrosis of bone marrow
• Chronic pain
• Heart failure
• Bacterial meningitis
• Bone infection due to Salmonella sp. (osteomyelitis)
• Cerebral hemorrhage
• Stroke
• Kidney failure
• Impaired vision or loss of vision
• Hearing loss

How is Sickle Cell Disease Treated?

The treatment methods for Sickle Cell Disease (SCD) are geared toward managing sickle cell crises and avoiding complications. The following treatment methods may be employed:

• Prophylactic antibiotics (typically penicillin) for children under 5 years of age to prevent life-threatening infections. If the child is allergic to penicillin, erythromycin may be prescribed instead
• Vaccinations in children to prevent infections 
• Surgical removal of the spleen (partial or complete) following episodes of splenic sequestration crises. Prophylactic penicillin or erythromycin (in case of an allergic reaction to penicillin) may need to be taken for the rest of one’s life following removal of spleen
• Medications to manage acute pain, on the advice of a healthcare provider
• Medications, such as morphine and oxycodone, for chronic pain
• Hydroxyurea for preventing sickle cell crises
• Monitoring of blood pressure, since even mild increases in blood pressure are associated with incidents of stroke in individuals with SCD
• Blood transfusions, in which healthy red blood cells from a donor are enriched and injected into an affected individual. This helps control or manage anemia
• Bone marrow or stem cell transplantation: This procedure is typically complicated and risky. It is mainly recommended for children under the age of 16
  • Stem cells from the bone marrow of a healthy, matching donor are injected into a recipient whose bone marrow cells have been destroyed with chemotherapy or radiation
  • This allows the healthy donor stem cells to migrate to the bone marrow of the individual with SCD. The healthy bone marrow cells generate normal blood cells
• Prophylactic medication to prevent thromboembolism in hospitalized adults

How can Sickle Cell Disease be Prevented?

Sickle Cell Disease (SCD) is an inherited disorder; no methods or guidelines exist to prevent this condition.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Keeping oneself hydrated, eating healthy food, avoiding exposure to very high/low temperatures, efficient stress management, and moderate exercise may help prevent sickle cell crises
• Since folic acid is necessary for the generation of new blood cells, taking folic acid supplements with the advice of a healthcare provider may be beneficial
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited genetic disorders such as SCD

Regular medical screening at periodic intervals with tests and physical examinations is strongly recommended in individuals diagnosed with Sickle Cell Disease.

What is the Prognosis of Sickle Cell Disease? (Outcomes/Resolutions)

The prognosis for Sickle Cell Disease (SCD) depends on the severity of the affected individual’s symptoms, the duration between sickle cell crises, the overall health status, and response to treatment. An individual’s access to good healthcare may also determine the outcome.

• Compared to a few decades back, the prognosis has improved significantly, owing to prenatal and newborn screening, vaccinations, and the use of prophylactic medication to prevent infections in children and reduce sickle cell crises
• If one does not develop complications, individuals with appropriate treatment can have an average life expectancy of over 50 years. Females with SCD are reported to live longer than males
• Individuals with severe complications have much shorter life expectancies; some children may not survive into early childhood or even infancy
• Also, the long-term prognosis in SCD individuals with sickle chest syndrome is worse compared to those without sickle chest syndrome

Additional and Relevant Useful Information for Sickle Cell Disease:

• Dehydration, increased acidity in blood, low blood volume, high altitude, and infection are known to increase the risk for sickle cell crises
• The areas in the world with the highest frequency of sickle cell genes are also regions where malaria is/was common