What is Sickle Cell Disease (SCD)?

Click on the tabs below to learn more about SCD including symptoms, causes, treatments and statistics. A glossary of terms associated with SCD is also provided.

Sickle cell disease (“SCD”) is an inherited genetic disorder caused by a mutation in the gene that encodes for hemoglobin, the protein in red blood cells that delivers oxygen throughout the body.

Red blood cells (“RBCs”) normally are disc-shaped, deformable and move easily through the microvasculature, using hemoglobin to carry oxygen from the lungs to the rest of the body (see Figure A below).

However, hemoglobin molecules in SCD patients stick together to form long fibers or rods. These fibers distort the shape of the RBCs, causing them to be less flexible and more likely to adhere to each other and to the walls of blood vessels, which severely impairs the flow of blood (see Figure B below). As a result, organs and tissues become deprived of oxygen, which can lead to severe pain, an accumulation of irreversible damage to organs, and an early death. Sickle cell disease is also an anemia since sickled RBCs are fragile and rupture more quickly than regular RBCs.

Images source: National Institutes of Health

What are the symptoms associated with SCD?

Signs and symptoms of sickle cell disease usually begin in early childhood. The hallmark of the disease is the recurring episodes of severe pain known as an acute crisis or vaso-occlusive crisis (“VOC”). VOC occurs when the proportion of sickled cells rises, leading to obstruction of small blood vessels and reduced blood flow to organs and bone marrow. This obstruction results in intense pain and tissue damage. Over a lifetime, the accumulated burden of damaged tissue leads to the loss of vital organ function and a greatly reduced lifespan. VOC is the leading cause for hospital admissions among SCD patients. The frequency, severity and duration of these acute crises can vary considerably from patient to patient and may range from once a year to more than monthly. Triggers for VOC episodes may include stress, dehydration, infection, or travel to a higher altitude, although the actual trigger is often unknown.

In addition to VOC, sickle-cell disease patients can suffer from many other complications, including:

  • Acute chest syndrome, a respiratory distress syndrome that may arise in the course VOC and a leading cause of death in SCD patients
  • Stroke (including silent stroke), which can result from a progressive narrowing of blood vessels, preventing oxygen from reaching the brain
  • Pulmonary hypertension and heart failure
  • Kidney dysfunction and chronic renal failure
  • Bone necrosis of the hip and other major joints
  • Frequent infections due to loss of splenic function and decreased immune function
  • Leg ulcers
  • Blindness
  • Increased rate of complications from pregnancy
  • Chronic deep muscle and bone pain even in the absence of acute vaso-occlusive pain

SCD is an inherited genetic disease affecting millions of people worldwide.

In a healthy individual, two copies of the gene for normal hemoglobin are inherited. These individuals are designated as having hemoglobin AA. When an individual inherits one copy of the abnormal gene and one copy of the healthy gene, that individual is designated as having hemoglobin AS and is considered to have “sickle cell trait” (SCT). Individuals with SCT generally do not have any of the signs or symptoms of SCD; however, they can pass along the abnormal gene to their children. In individuals with SCD, both copies of the hemoglobin gene are abnormal (ss). In other words, these individuals do not have any copies of the normal hemoglobin A gene.

There are several genetic variants of SCD. The most common types are designated as hemoglobin SS (HbSS), hemoglobin SC (HbSC) and hemoglobin S Beta Thalassemia (HbSβthal). Individuals with HbSS have the most severe form of SCD and are responsible for the majority of hospitalizations. HbSC is generally a more mild form of SCD, although these individuals can still experience severe VOC. The severity of SCD in HbSβthal individuals depends on the severity of the co-inherited beta-thallasemia gene. When no beta globin is produced by the beta-thallasemia gene, the condition is very similar to that of individuals with HbSS.

Crisis (Pain) Management

Currently, there is no disease-modifying treatment for an ongoing painful crisis. Patients are treated symptomatically for pain using intravenous opioids until the crisis has settled, typically within 4 – 5 days, but crises may last a week or longer. Painful crises are also treated with hydration, and in some cases, blood transfusion. For crises not requiring hospitalization or for daily pain, patients can manage on non-steroidal anti-inflammatory drugs (“NSAIDs”) and other prescription oral medications.

In 2006, there were approximately 98,000 emergency department visits for VOC among SCD patients with the HbSS genotype (not including SCD patients with HbSC or Hb Sβthallasemia genotypes) according to ICD-9 codes reported in the Healthcare Cost and Utilization Project (HCUP) report published in the Journal of the American Medical Association in 2010.

Disease Management

Typically, disease management for SCD patients is focused on controlling complications and limiting the number and severity of painful crises.

The only drug that is FDA labeled for the treatment of sickle-cell anemia is hydroxyurea (“HU”). In controlled clinical trials the chronic administration of HU was associated with a decrease in the number and severity of VOC (Charache S, Terrin ML, Moore RD, et al., May 1995) and more recent studies suggest HU may also confer a longer term survival benefit (Steinberg MH, Barton F, Castro O, et al., April 2003, and; Voskaridou et al., Blood, March 2010).

Hydroxyurea is also used as a chemotherapy agent and there is some concern that long-term use may be harmful, but longitudinal studies suggest this risk is likely to be small and that the benefits of HU outweigh the risks.

Sickle Cell Disease Statistics

  • Sickle cell disease affects tens of millions of people worldwide.
  • Sickle cell disease is the most common inherited blood disorder in the United States.
  • Sickle cell disease is estimated to affect approximately 90,000 – 100,000 Americans.
  • Sickle cell disease is estimated to occur in 1 of every 500 African American births and 1 of every 36,000 Hispanic American births.
  • Sickle cell disease leads to shorter life expectancy.
  • The estimated annual cost of medical care for patients with SCD in the U.S. exceeds $1.0 billion.
    • It is estimated that 70% of sickle cell disease hospitalizations are covered by public insurance.
    • It is estimated that undiscounted health care costs for a SCD patient reaching 45 years of age can total more than $950,000.
    • In 2005-2006, there were approximately 98,000 emergency department visits in the U.S. for VOC among a cohort of 21,112 SCD patients with the HbSS genotype (not including HbSC or Hb Sβthallasemia genotypes).
    • Episodes of sickle cell crisis typically last 4 – 5 days, but may last a week or longer.
    • It is estimated that the number of untreated sickle cell crisis events is substantial and in the hundreds of thousands in the U.S. each year.

SCD Glossary

Below is a list of commonly used terms associated with sickle cell disease.

“ACS” – Acute Chest Syndrome

ACS is a serious complication which can arise from sickle cell disease and is a leading cause of death in sickle cell disease patients. The underlying cause of ACS is believed to be pulmonary hypoxia or lung injury, which itself results from varied causes, including pulmonary infection, fat emboli and rib infarction. ACS is typically characterized by a pulmonary infiltrate evident on a chest radiograph in combination with clinical symptoms, such as fever, cough, chest pain, shortness of breath, wheezing, hypoxemia, increases leukocytosis or worsening anemia. It is estimated that in the U.S., there are nearly 10,000 episodes of acute chest syndrome associated with sickle cell disease every year.

“Hb Sβthallasemia” - Hemoglobin S Beta Thalassemia

Individuals with Hb Sβthallasemia produce a lower number of RBCs than normal healthy individuals and some of their RBCs are crescent or sickled shaped. The severity of the disease can vary from milder forms with very few symptoms to very severe, with the severity dependent on the severity of the co-inherited beta-thallasemia gene. When no beta globin is produced by the beta-thalassemia gene, the condition is most similar to that of individuals with HbSS.

“HbSC, SCD-SC, SC” – Hemoglobin SC

Individuals with HbSC usually experience milder symptoms that those with HbSS and Hemoglobin SC Disease is the second most common type of SCD. Patients with HbSC have 1 sickle cell hemoglobin gene and one hemoglobin C gene, which is another type of abnormal hemoglobin.

“HbSS, SCD-SS, SS” – Hemoglobin SS

Individuals with HbSS have the most severe form of SCD and HbSS disease is the most common type of SCD. Patients with HbSS have two sickle cell hemoglobin genes and no normal hemoglobin genes.

“HU” – Hydroxurea

Hydroxyurea is in a class of medications known as antineoplastic agents and is the only drug that is FDA labeled for the treatment of sickle-cell anemia. HU is also utilized as a chemotherapeutic agent for various types of cancer. HU treats sickle cell anemia by changing RBCs so that they are less likely to sickle into an abnormal shape. In controlled clinical trials the chronic administration of HU was associated with a decrease in the number and severity of VOC (Charache S, Terrin ML, Moore RD, et al., May 1995), and more recent studies suggest HU may also confer a longer term survival benefit. (Steinberg MH, Barton F, Castro O, et al., April 2003) (Voskaridou et al., Blood, March 2010)

“PRV” – Priority Review Voucher

The Food and Drug Administration Safety and Innovation Act was signed into law July 11, 2011 and Section 908 of the Act includes a Rare Pediatric Disease Priority Review Voucher Incentive Program. This entitles the sponsor of a “rare disease application” to a priority review voucher upon approval of their New Drug Application (“NDA”) which can be utilized for the expedited review of a subsequent NDA for the sponsors’ second product candidate. The PRV can be transferred, including by sale, and entitles the holder to priority (6-month) review of a new drug application. Among other requirements, the rare pediatric disease application must target a rare pediatric disease, a disease that primarily affects individuals from birth to 18 years and that is a rare disease or condition.

“RBC” – Red Blood Cell(s)

RBCs are the most common type of blood cell in the human body are the organism’s principal way of delivering oxygen to the body’s tissues through the circulatory system. RBC’s contain hemoglobin, which is the protein that can bind and deliver oxygen throughout the body and which gives blood its color.

“SCD” – Sickle Cell Disease

SCD is an inherited genetic disorder caused by a mutation in the gene that encodes for hemoglobin, the protein in red blood cells that delivers oxygen throughout the body. Red blood cells (“RBCs”) normally are disc-shaped, deformable and move easily through the microvasculature, carrying oxygen from the lungs to the rest of the body, but hemoglobin molecules in SCD patients stick together to form long fibers or rods. These fibers distort the shape of the RBCs, cause them to be less flexible while traveling through the blood vessels and make them more likely to adhere to each other and to the walls of blood vessels, which impairs the flow of blood. As a result, organs and tissues become deprived of oxygen, which can lead to severe pain, irreversible damage to organs and an early death. Sickle cell disease is also an anemia since sickled RBCs are fragile and rupture more quickly than regular RBCs.

“VOC” – Vaso-Occlusive Crisis

The hallmark of SCD, VOCs are recurring episodes of severe pain. VOC occurs when the proportion of sickled cells rises, leading to obstruction of small blood vessels and reduced blood flow to organs and bone marrow. This results in intense pain and tissue damage. Over a lifetime, the accumulated burden of damaged tissue leads to the loss of vital organ function and a greatly reduced lifespan. VOC is by far the leading cause for hospital admissions among SCD patients. The frequency, severity and duration of these acute crises can vary considerably from patient to patient and may range from once or twice a year to more than monthly. Triggers for VOC episodes may include stress, dehydration, infection, or even travel to a higher altitude, although the actual trigger is often unknown.