Type of disease

Sickle cell disease (SCD) is a hereditary blood disorder that is caused by an abnormality in the hemoglobin in red blood cells. Hemoglobin is a protein that is found in red blood cells, and it plays an important role in carrying oxygen to all parts of the body.

Hemoglobin structure and function

Hemoglobin is the substance that creates the red color of red blood cells. Red blood cells contain a large number of hemoglobin molecules. Hemoglobin is a protein that is made up of four protein chains; two alpha globin chains and two beta globin chains. These four protein chains each contain an iron atom to which oxygen or carbon dioxide can attach itself. This means that hemoglobin has four elements that can bind oxygen or carbon dioxide, so that the hemoglobin can transport the oxygen or carbon dioxide through your body in the bloodstream.

Oxygen is a very important fuel for the cells in your body. You breathe in the oxygen through your lungs, where it crosses into the bloodstream. In the blood, the oxygen binds to the hemoglobin in the red blood cells. The red bloods cells are transported across the body, delivering oxygen to cells all over the body. This is how your organs, such as your brain, kidneys, liver, or muscles, get the energy they need. At the same time, waste (carbon dioxide) from the cells binds to the hemoglobin vacated by the oxygen. The red blood cells are then transported through the body back to your lungs, where they discharge the carbon dioxide so that it can be breathed out.

So, hemoglobin both supplies fuel (oxygen) for the cells and disposes of the waste (carbon dioxide) from the cells. The hemoglobin of children and adults is referred to as hemoglobin A1 (where A stands for Adult). Newborn babies have a different kind of hemoglobin that is called hemoglobin F (F stands for Fetal). This hemoglobin is structured differently to allow the baby to absorb sufficient oxygen from the mother's blood while it is still in the womb. After birth, the amount of hemoglobin F is gradually converted into hemoglobin A1.

Hemoglobin can, however, also develop differently, such as when the beta globin chains have a different structure or when the body does not produce enough alpha globin chains. If this happens, you have a disorder where you make an atypical kind of hemoglobin, which is called hemoglobinopathy.

What is wrong with the hemoglobin in cases of sickle cell disease?

When you have sickle cell disease, your hemoglobin is atypical (hemoglobinopathy). One of the hemoglobin chains, i.e. the beta globin chain, is structured differently. This is caused by a mutation in the beta globin gene. As a result of this mutation, the hemoglobin has a different shape. This abnormal type of hemoglobin is called hemoglobin S (where the S stands for Sickle cell). The problem is that hemoglobin S (HbS) potentially binds to other HbS within the red blood cell, causing the red blood cell to become abnormally shaped, namely the shape of a sickle. These sickle-shaped red blood cells are less flexible than normal red blood cells.

The development of sickle cells is influenced by changes in the amount of oxygen in the blood and the pH-level of the blood, as well as by changes to the concentration of osmotic agents in the blood (osmolarity). Such changes can occur in cases of fever, an infection, pain, at high altitude (such as in the mountains) or in cold environments, dehydration and (physical) stress. It is therefore very important to prevent and avoid such circumstances as much as possible.

The following gives a summary of the changes that can occur in the development of hemoglobin.

Hemoglobin type	Globin chains	Globin chains	Manifestation
Normal situation
Hemoglobin A1: HbA1	2 alpha globin chains	2 beta globin chains	Normal Hb
Hemoglobin A2: HbA2	2 alpha globin chains	2 delta globin chains	Normal level is under 3,5%
Hemoglobin F: HbF	2 alpha globin chains	2 gamma globin chains	Normal in newborns
Types of sickle cell disease (SCD) and thalassemia
Only hemoglobin S: HbSS	2 alpha globin chains	2 mutated beta globin genes-> causing 2 HbS beta globin chains	Homozygote SCD, HbSS- SCD
Both hemoglobin S and hemoglobin C: HbSC	2 alpha globin chains	2 types of mutated beta globin genes-> causing 1 S beta globin chain and 1 C beta globin chain	HbSC- SCD (mild anemia, clinical course mostly milder then HbSS-SCD)
Both hemoglobin S and hemoglobin E: HbSE	2 alpha globin chains	2 types of mutated beta globin genes-> causing 1 S beta globin chain and 1 E beta globin chain	HbSE- SCD (mild anemia and mild splenomegaly)
Beta thalassemia major	2 alpha globin chains	2 mutated beta genes-> causing a shortage of beta globin chains	Severe clinical course, dependance on bloodtransfusions
Beta thalassemia intermedia	2 alpha globin chains	1-2 mutated beta globin genes -> causing sometimes a shortage of beta globin chains	Variable clinical course, depandance on bloodtransfusions occurs
Beta thalassemia minor	2 alpha globin chains	1 mutated beta globin gene	No clinical consequences, only carrier
Severe alpha thalassemia: hemoglobin H, HbH	0-1 alpha globin chain	4 beta globin chains	Occurs in patients with 3-4 mutated alpha globin genes and still some alpha globin chain production
Severe alpha thalassemia: hemoglobin Barts, HbBarts	4 mutated alpha globin genes leading to 0 alpha globin chains	4 gamma globin chains	Very severe alpha thalassemia, often fatal before birth.
Mild alpha thalassemia	1-2 mutated alpha globin genes, less alpha globin chain production	4 beta globin chains	No clinical consequences, only carrier
Other forms of alpha thalassemia	Rare mutations of alpha globin genes	4 beta globin chains	Variable clinical presentation

The diagnosis of SCD applies in case of various forms of hemoglobinopathies. SCD will, for example, be diagnosed in cases of:
• HbSS (homozygote SCD or sickle cell anemia), roughly 70% of SCD patients.
• HbSC disease (compound heterozygote sickle cell anemia), roughly 25% of patients,
• a different kind of compound heterozygote sickle cell anemia (such as HbS/beta thalassemia, HbS/D Punjab, HbS/O Arab) in roughly 5% of patients.