Sickle cell disease

Hemoglobin is a component of red blood cells that enables them to capture oxygen in the lungs and release it into our tissues, thus benefiting all our organs. It is a protein made up of four subunits called “globins”. Normal adult hemoglobin (HbA) contains two α-globins and two β-globins. Diseases related to hemoglobin are called hemoglobinopathies. This term encompasses sickle cell disease, caused by an abnormality in the quality of hemoglobin, as well as thalassemias, which result from an insufficient quantity of one or several globins. Each year, between 300,000 and 500,000 births worldwide are affected by a severe form of hemoglobinopathy. Sickle cell disease is a genetic disease caused by the transmission from father and mother, of a mutation of β-globin, which causes the presence of an abnormal hemoglobin.

The different forms of sickle cell disease are also called "major sickle cell syndromes." These syndromes encompass various combinations of mutations responsible for syndromes of varying severity, both clinically and biologically. The most common form is due to the transmission, from both parents, of a mutation causing the production of a β-globin designated "S" (for "sickle"): affected individuals are therefore called "homozygous SS" and suffer from sickle cell anemia. The second most common form involves the inheritance of the "S" mutation and another mutation designated "C": these individuals are called "compound heterozygous SC". Other, rarer compound heterozygous forms also exist, including the following ones: HbS/βthal, HbS/HbD-Punjab, and HbS/HbO-Arab.

Due to its β-globin S, hemoglobin S (or HbS) has a detrimental characteristic: when deprived of oxygen, it forms aggregates (fibers) within red blood cells, causing them to take on a sickle shape: this is sickling. These hemoglobin S fibers also make red blood cells more fragile, leading to their rupture within blood vessels: this is intravascular hemolysis. Finally, these aggregates, called "HbS polymers," also make red blood cells more rigid, thus promoting their blockage in small blood vessels: this is vaso-occlusion. Research has shown that this vaso-occlusion is generally precipitated by the adhesion of white blood cells to the walls of small blood vessels called "postcapillary venules," which facilitates the blockage of red blood cells.

As soon as the newborn's hemoglobin, fetal hemoglobin (hemoglobin not containing β-globin), is replaced by the hemoglobin that will remain throughout life, adult hemoglobin (containing β-globin), complications can arise. Sickle cell disease is therefore characterized by the possible occurrence, as early as 3 months of age, of acute complications of varying severity, and by the progressive development of degenerative lesions and persistent complications (chronic complications). These can be life-threatening. The frequency of each type of acute complication varies throughout a patient's life and differs considerably from one patient to another.

Harmful consequences are numerous:

  • a consistently low hemoglobin level due to hemolysis: this is chronic hemolytic anemia. It is accompanied by potential consequences, including worsening anemia or the development of gallstones

  • increased susceptibility to infections by encapsulated bacteria (primarily Pneumococcus and Salmonella) due to hyposplenism (impaired spleen function)

  • vaso-occlusive phenomena, dominated by painful vaso-occlusive crises (VOCs) of the bone, which cause (ischemic) lesions in organs

  • damage to the large vessels (macrovessels) in the brain that can lead to strokes. These lesions can be detected in children (using transcranial Doppler and Magnetic Resonance Imaging) in order to implement preventive therapy based on transfusion exchange protocols.

Following the discovery of the mutation, usually during a neonatal diagnosis, specific management will help reduce the frequency of complications and mortality associated with this serious disease. This management is based on the following pillars:

  • Prevention

    Antibiotic therapy and an enhanced vaccination program help prevent infections, folic acid (vitamin B9) supplementation aims to prevent the worsening of anemia, and regular consultations and examinations allow for monitoring the patient's health and adjusting treatments if necessary. Moreover, the medical team teaches parents early on how to detect certain complications.

  • Hydroxyurea (Siklos or Hydrea)

    Ce médicament est le plus prescrit au monde, afin de réduire la fréquence et l’intensité de certaines complications associées à la drépanocytose, dont la CVO. Ses modes d’action sont multiples :
    - il empêche la formation de polymères d’HbS, en causant la production d’hémoglobine fœtale.
    - il rend les cellules sanguines et celles des vaisseaux sanguins moins adhérentes, en réduisant le taux d’hémolyse et en agissant sur les microparticules (produites notamment par bourgeonnement des globules rouges).
    - il défavorise la diminution du diamètre des vaisseaux sanguins, en libérant du monoxyde d’azote.

  • Transfusion

    This involves infusing normal red blood cells to correct worsening anemia and to lower the percentage of hemoglobin S. It therefore provides a supply of normal hemoglobin, improves organ oxygenation, and reduces the risk of vaso-occlusion.

  • Bone Marrow Transplantation (to cure the disease)

    Bone marrow transplantation, or hematopoietic stem cell transplantation, is currently the only well-established curative treatment for sickle cell disease. Bone marrow is the tissue located at the core of bones: it produces all blood cells (red blood cells, white blood cells, and platelets). The principle involves removing the patient's bone marrow with medication, then intravenously infusing—like a transfusion—stem cells from a compatible donor. These cells will integrate into the bones and produce normal blood cells. When the donor is a perfectly matched sibling, it is called a geno-identical transplantation. However, more recent protocols also allow for so-called haploidentical transplantation, using a partially compatible donor. This treatment can lead to complications (severe infections, transplant rejection, or graft-versus-host disease) and is therefore primarily offered for severe forms of the disease.

  • Gene therapy (to cure the disease)

    As already mentioned, fetal hemoglobin disappears shortly after birth, and is replaced by adult hemoglobin. However, in some people, this fetal hemoglobin is present at abnormally high levels in adulthood: they are said to have hereditary persistence of fetal hemoglobin (HPFH). In the 1980s, physicians noticed that in cases of HPFH, patients living with sickle cell disease had less severe symptoms. In the 2010s, researchers discovered how certain DNA mutations could lead to this HPFH, while other researchers discovered how to generate mutations relatively easily. Based on this knowledge, clinical trials were launched: red blood cell-producing cells are taken from patients living with sickle cell disease to generate the aforementioned mutations. Then, after eliminating the red blood cell-producing cells from these patients, the cells carrying the mutations are injected to the patients, thus enabling the production of red blood cells containing high levels of fetal hemoglobin, resulting in a cure. This innovative therapy, which costs $2.2 million per patient, was approved in 2023 by the FDA (Food and Drug Administration) in the United States, but in France, it was authorized in 2024 for cases of β-thalassemia requiring transfusions, but not for sickle cell disease.

Source: Dr. Yohann GARNIER and Dr. Scylia ALEXIS-FARDINI (UMR_S 1134 Inserm/UA and Transversal Unit of Sickle Cell Disease of the University Hospital of Guadeloupe), in March 2026..

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