Sickle cell disease: a disease of the blood. Sickle cell disease: a genetic disease widespread in the world. Sickle cell disease is a genetically inherited disease (autosomal recessive inheritance). Clearly, the disease is transmitted by both parents, it is of course not contagious. To be sick, the child must receive from each of these two parents a mutated allele of the gene governing the structure of hemoglobin, the protein that transports oxygen to the blood. If he receives only one, he will not develop the disease but can transmit it if he has a child with a person in the same case like him. Two “healthy carriers” then have a one in four chance of having a sick child together.

It is a disease of the blood, and more particularly of hemoglobin. Red blood cells are deformed and have difficulty circulating in the blood and can sometimes become blocked in the blood vessels. This disease has emerged independently in Africa and India. It is also found in southern Italy, Greece, the Near East, the West Indies, and Brazil, and nowadays in almost all the world.Sickle cell disease

1 – Understanding and Definition of Sickle Cell Disease

Sickle cell disease, also known as sickle cell anemia, is an inherited disease affecting the hemoglobin of red blood cells. This protein is essential to respiratory function: it is it that allows the transport of oxygen in our body. It is also involved in the elimination of carbon dioxide.

In people with sickle cell disease, hemoglobin is abnormal. When the oxygen concentration of the blood decreases, it deforms the red blood cells (or red blood cells) which take the form of sickles, instead of being biconcave. This results in several characteristic symptoms of the disease, the most common of which are chronic anemia, painful vaso-occlusive seizures, and increased susceptibility to infections.

*** Genetic alteration of the hemoglobin responsible for the disease

Sickle cell disease is due to the mutation of a gene located on chromosome 11, coding for one of the two types of proteins that form hemoglobin: beta-globin. Because of this mutation, sickle cell hemoglobin (Sickle hemoglobin S, English sickle) tends to polymerize when the oxygen concentration in the blood is low (hypoxia). The hemoglobin S polymers then deform the red blood cells and give them this characteristic shape of a sickle.

Rigid, red blood cells can block, obstruct the flow of blood through small blood vessels and compromise the oxygenation of tissues. This poor blood circulation is at the origin of vaso-occlusive crises (CVO).

Hemoglobin S polymers also weaken red blood cells that undergo early destruction (hemolysis). Their lifespan thus goes from about 120 days to only twenty days. This results in a low level of red blood cells in the blood of sickle cell disease which results in chronic anemia.

The spleen of sickle cell patients is also prematurely injured by vaso-occlusions. It is also very much in demand to ensure the hemolysis of falciform red blood cells. It no longer assures its role in the control of certain bacterial infections, especially pneumonia and meningitis.

Sickle cell disease is an autosomal recessive genetic disorder: for it to be declared, each parent must transmit a mutated allele to their child. For healthy parents, the risk of having a child with the disease is one in four. For a couple with sickle cell disease and a healthy carrier, the risk is one in two.

2 – The Different Types of Sickle Cell Disease

There are two types of sickle cell disease, the homozygous form, and the heterozygous form.

*** Homozygous sickle cell disease

The form of the disease occurs before the age of two, between 12 and 18 months, and is characterized by:

– jaundice;

– a pale complexion;

– abdominal pain;

– anemia;

– Sensitivity to infections.

*** Heterozygous sickle cell disease

The heterozygous form does not manifest itself. Indeed, the person carries the disease on a single gene. The person can give birth to a sickle cell child if the other parent is also carrying the gene.

3 – The Symptoms of Sickle Cell Disease

We observe highly variable and often unpredictable symptoms. The main symptoms of sickle cell disease are hemolytic anemia, painful seizures, and increased susceptibility to infections. They can appear from the age of 4 months. However, these symptoms vary a lot from one patient to another and their intensity changes over the years.

– Anemia

Anemia is often the first sign of the disease. It results in pallor and chronic fatigue, sometimes jaundice (jaundice). The anemia is likely to worsen abruptly in case of overactivity of the spleen in the destruction of red blood cells. This is called acute splenic sequestration. Stopping the production of red blood cells can also worsen anemia. These so-called aplastic seizures can be caused by parvovirus B19, benign in normal times. Despite these possible complications, chronic anemia is generally fairly well tolerated by sickle cell patients.

– The Vaso-Occlusive Crises

Caused by the filling of small blood vessels, these crises cause acute pain often extremely violent. They particularly affect the bones, the joints of the arms and legs, the back or the chest. In toddlers, the seizure usually manifests as painful swelling of the hands and feet (foot-hand syndrome). These vascular occlusions can cause major complications.

For example, strokes are common in sickle cell patients, especially in children. These strokes manifest themselves in a very variable way (paralysis, headaches, aphasia, balance disorder …) and are usually transient. In some cases, however, they leave serious intellectual and/or motor sequelae.

Another example of a serious complication is an acute thoracic syndrome. In this case, vaso-occlusion affects the lung and compromises the oxygenation of the entire body. This results in the patient with breathing difficulties and pain in the chest, sometimes accompanied by a fever.

Finally, the repetition of vaso-occlusions can lead, in the long run, to the necrosis of certain tissues such as bone (osteonecrosis of the femoral head) or organs such as the spleen.

– The Sensitivity to Infections

Infections exacerbate other manifestations of sickle cell disease (worsening anemia and promoting vascular occlusions). On the other hand, they always represent a risk of mortality (sudden sepsis), especially in children with weakened defense mechanisms.

– Other Complications

Over the years, all these manifestations of the disease put the body to the test. Patients are often affected by stunting and later puberty. Various chronic complications can occur in adults. They are likely to affect almost all organs including the kidney (renal insufficiency), the osteoarticular system (osteoarthritis, osteoporosis), the eye (intraocular hemorrhages), the liver, the lungs (pulmonary arterial hypertension), or the vesicle gallstone (stones).

*** Notes and summary on the symptoms of sickle cell disease

In its homozygous form, sickle cell disease is manifested in 12-18 months of age by jaundice, pallor, a large liver, and a large spleen. Painful abdominal tendencies and limb pain are characteristic. Sometimes the doctor mentions a crisis of R.A.A. (acute rheumatic fever) or appendicitis. Other symptoms are less suggestive: recurrent respiratory infections, convulsions, coma, paralysis, heart failure, hematuria, etc.

The child with a major sickle cell syndrome is very exposed to common or severe infections: pneumopathies, meningitis, septicemia, osteomyelitis, etc. These infections are severe especially in children with sickle cell under 5 years.

They also cause complications specific to sickle cell disease:

– Aggravation of anemia (pallor, asthenia, respiratory discomfort, jaundice);

– Thromboembolic vascular accident (hemiplegia, pulmonary infarction …);

– Crisis of deglobulization (transient medullary aplasia);

– Painful crises …

The acute splenic sequestration is translated in a child of fewer than 5 years by acute anemia with a huge spleen of sudden appearance. A transfusion is urgently needed.

4 – Diagnosis of Sickle Cell Disease

To establish the diagnosis of the disease, the doctor recommends 3 reference exams:

– Electrophoresis of hemoglobin allows diagnosis;

– The blood smear makes it possible to observe red blood cells in the form of a sickle;

– The NFS (blood count) shows a hemoglobin level between 7 and 9 g / dl.

In France, neonatal screening is routinely performed in children of parents from populations most affected by the disease. It makes it possible to determine whether the child is a healthy or sick carrier in order to start as soon as possible the preventive treatment of anemia and infectious complications.

Prenatal diagnosis can be proposed during pregnancy in a couple at risk. It involves looking for the mutated allele in the fetal DNA (from placenta cells as early as 12 weeks of pregnancy or by amniocentesis around the 16th week). It is also possible to perform a preimplantation diagnosis (PGD) on embryos obtained by in vitro fertilization, but this process is cumbersome and highly regulated.

5 – Prevention and Treatment of Sickle Cell Disease

For most patients, the management of sickle cell disease is based on the prevention of complications and regular medical follow-up.

*** Prevention of complications

First and foremost, prophylaxis of infectious risk consists of preventively administering antibiotics and strengthening the vaccination program, especially in infants and young children. Folic acid and iron supplements are also prescribed to boost red blood cell production and prevent anemia.

A healthy lifestyle and a balanced diet are essential. To reduce the risk of painful crises, good hydration is necessary. Exposure to extreme temperatures or temperature variations should also be avoided. Too intense efforts related to the practice of extreme sports and endurance are to be avoided. To ensure a sufficient supply of oxygen, it is also recommended for patients to avoid poorly ventilated rooms and stays at more than 1500 meters altitude where oxygen is becoming scarce. Sickle cell patients should also wear loose clothing that does not cut blood circulation.

Regular medical monitoring makes it possible to evaluate the evolution of the disease and the damage it causes to the organs. The renal and respiratory functions are particularly followed as well as the state of the eye. A cerebral ultrasound (transcranial Doppler) is regularly performed to monitor blood flow in the arteries of the brain. Too fast flows indicate a risk of stroke and lead to the establishment of a transfusion prevention program.

*** Blood transfusions

Blood transfusion is an important tool in the management of sickle cell disease. It consists of transfusing the patient with the blood of a compatible healthy donor, thus making it possible to restore an acceptable level of red blood cells in case of aggravated anemia. In case of serious complications, transfusion exchanges, also called erythrocyte exchanges, can be put in place: the patient’s blood is partially “replaced” by that of a healthy donor. These transfusions reduce the risk of stroke. However, repeated transfusions can lead to erythrocyte alloimmunization: the patient’s immune system reacts against the blood of the donor, considered to be foreign. The beneficial effect of transfusion (and future transfusions) is compromised. This phenomenon occurs especially when patients and donors are of different ethnicities, a common situation in France.

*** Management of painful seizures

In the event of a vaso-occlusive attack, analgesics relieve pain. If the pain persists, hospitalization is necessary. The strength of the analgesics will then be increased until the administration of morphine or opioid derivatives for the most resistant pains. Taking analgesic is sometimes supplemented by oxygen therapy

To reduce the occurrence of painful attacks, hydroxycarbamide (or hydroxyurea) may be prescribed. This medication works on several levels in the prevention of vaso-occlusions. It makes it possible in particular to increase the production of hemoglobin present in low concentration in the adult, the so-called fetal hemoglobin. Usually found in the fetus and newborn, it reduces the polymerization of hemoglobin S. Hydroxycarbamide is particularly effective in children. This treatment has greatly improved their quality of life. However, its effectiveness may decrease with age, and not all adult patients respond to this treatment. In addition, hydroxycarbamide can lead to (reversible) fertility problems in men.

*** The bone marrow transplant

The only curative treatment currently available for sickle cell disease is bone marrow transplantation. This marrow indeed contains stem cells that give rise to blood cells, including red blood cells. Concretely, the stem cells of the patient’s marrow are destroyed and replaced by those of a compatible healthy donor, often a brother or a sister. However, there is no compatible donor for all patients. In addition, this procedure, very heavy and expensive, is not completely without risks. It is reserved for the most severe forms of the disease, especially in cases of cerebral vasculopathy in children. Around twenty children benefit each year in France.

*** Towards new drugs

Reducing the impact of falciform red cell hemolysis on the body is one of the goals. The destruction of red blood cells leads to the release of hemoglobin in the body. However, this free hemoglobin destroys nitric oxide (NO), a molecule that allows vessels to dilate and therefore have good blood flow. Hemolysis of red blood cells also releases heme, a deleterious component for the endothelium of vessels. The search for drugs capable of neutralizing free hemoglobin, heme, or preserving the action of NO is therefore actively pursued. Other work aims to prevent the dehydration of the red blood cell or to reduce the oxidative stress caused by the polymerization of hemoglobin S.

Moreover, progress in understanding the pathophysiology of the disease has shown that sickle cell disease is not only a red blood cell disease: vascular endothelium and white blood cells (especially neutrophils) play a role in vascular occlusion phenomena. Drugs affecting these abnormal interactions between red blood cells, white blood cells, and blood vessel walls are under development.

As a Conclusion on Sickle Cell Disease

Sickle cell disease affects the hemoglobin of red blood cells. This widespread genetic disease is manifested by anemia, painful crises, and an increased risk of infections. Current treatments have greatly increased the life expectancy of affected patients, but they remain limited. Research is continuing its efforts to improve or even treat the disease at its source, where red blood cells are born.

The disease can have varying repercussions depending on its severity. Permanent anemia is a handicap in everyday life as well as pain crises and unpredictable complications. Psychological support can be recommended to better live with his illness, both for the patient and those around him.

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