Sickle Cell Disease

What is sickle cell disease?

Sickle cell disease (SCD) is a group of inherited disorders that affect hemoglobin, a protein found in the red blood cells (RBCs). [1]  Normal hemoglobin (HbA) carries oxygen to the various cells of the body. [2] Healthy RBCs are disc-shaped and flexible allowing them to easily squeeze through small blood vessels. [3]  In people with SCD, due to a change  in the hemoglobin gene, abnormal hemoglobin protein (HbS) is made. This abnormal hemoglobin (HbS) is not as good at carrying oxygen efficiently as normal hemoglobin. It sticks together and forms stiff rods that change  the RBCs into a sickle shape (curved or half-moon shaped). [3, 4] These sickled RBCs are no longer flexible  and cannot move easily, sticking to the walls of blood vessels. [4] They also trap white blood cells and platelets, and block blood vessels. [5] This stops  blood flow and prevents oxygen from reaching the cells that are connected to  blood vessels causing severe pain.

Sickle cells are also destroyed in the spleen because of their shape and stiffness. The spleen normally removes old blood cells and infectious agents from the blood. The sickle RBCs are also removed from circulation and destroyed. This causes a lot r of RBCs being removed from the body leading to a constant shortage of RBCs and chronic anemia. [6] People with SCD often have issues with their spleens. When sickled RBCs clog the spleen, in addition to cutting off the oxygen damaging it, they can block blood from flowing through the spleen to remove infectious agents resulting in an increased risk for infections. [6]

How is SCD inherited?

Genes, found in your DNA, determines what type of hemoglobin proteins are made. SCD is caused by a change in the hemoglobin gene that results in abnormal hemoglobin HbS. [7] Each gene has two copies – one from the mother and one from the father. Therefore, a person will have

• ‘Sickle cell trait’ if they inherit just one abnormal gene. They will typically not have any symptoms but will be "carrier" of the disease and can pass this gene to each child they have. If both parents are carriers there's a 1 in 4, or a 25 % chance of having a child with SCD. [7,8]
• SCD forms if they inherit two abnormal genes, one from each parent.

What are the risk factors for SCD?

Factors that increases risk for the SCD:

• Having a family history of SCD
• Being of African, Middle Eastern, Indian, and the Mediterranean descent. [7-9]

Having ‘sickle cell trait’ protects against malaria. [1,9] As a result, SCD is most common in regions affected by malaria, such as parts of Africa, the Middle East, India, and the Mediterranean region. [1] However, immigration from these regions to other parts of the world has led to the distribution of SCD globally. [1]

What are the symptoms and complications of SCD?

SCD can affect many different parts of the body. [4]

The most common symptoms of SCD are pain crises (often called vaso-occulsive episodes or vaso-occlusive), which happen when sickled RBCs block blood vessels which results in less oxygen being delivered to different parts of the body. [4]  Without oxygen the tissue begins to die. These crises are extremely painful, can happen at any time,[10,11] and often require hospitalization. [1,4] They are often triggered by being exposed to cold, stress, strenuous exercise, or dehydration. [12]

In addition to pain crises, blocked blood vessels can have other effects throughout the body such as:

• Acute chest syndrome: This occurs when the sickled cells block the flow of oxygen to the lungs leading to fever, pain, and violent cough.
• Splenic sequestration: This occurs when sickled cells get stuck in the spleen leading to a sudden decrease in hemoglobin which can be life-threatening. The spleen can also become enlarged, painful, and permanently damaged leading to increased risk of infection especially in children. Infection is the major cause of death in children younger than age five in this population.
• Priapism: prolonged, painful erections; repeated episodes may cause permanent damage and erectile dysfunction.
• Stroke: Blockage of blood and oxygen to the brain can result in severe brain damage. Both adults and children with SCD have increased risk of stroke. [4, 7]

Additionally, over time, repeated blockages and pain crises also cause long-term (chronic) pain and damage to vital organs and tissues. [4] Long-term medical issues associated with SCD are shown in the diagram below. [4,7,13,14] 

How is SCD treated?

Treatment: Most of the current treatments for SCD aim to reduce the number of painful crises. 

• Medicines for sickle cell pain may not be available in every country. [4]
  • Hydroxyurea (hi-droxy-you-ree-ah) is a tablet taken by mouth to decrease the number of pain crises by decreasing the concentration of abnormal hemoglobin in RBCs[15]
  • L-glutamine (el-gloot-a-meen) is a powder taken by mouth that decreases the number of pain crises by reducing damage to sickled RBCs[15]
  • Crizanlizumab (crizz-an-lizz-oo-mab) is a medicine given by an infusion into the vein. It reduces the number of pain crises by stopping RBCs from sticking to the walls of the blood vessels. [15]
  • Voxelotor (vox-el-oh-tor) is a tablet taken by mouth. It attaches to abnormal hemoglobin and stops it from forming into sickled RBCs. This helps to raise the level of hemoglobin. [15]
• Supportive care such as drinking lots of water, staying warm, staying distracted, and treating underlying infections can work for some. [16]

Prevention: preventative measures to lower the risk of certain complications can include:

• Vaccines and antibiotics (usually penicillin) to protect against infections[4]
• Blood transfusions to prevent stroke especially in children. [15]

Cure: Currently a stem cell transplant or bone marrow transplant (BMT) is the only way of curing SCD. However, BMT is a high-risk strategy. If successful, it can cure the disease. If it fails it can have severe consequences such as graft-versus-host disease (donated stem cells attack the body), or rejection of the donor stem cells by the body after the transplant. [4,16] 

Research: Researchers are continuing to look for more effective treatment options for patients with SCD in ongoing clinical trials.