Sickle Cell Anaemia

What is sickle cell?

Sickle cell disease, also called sickle cell anemia or just sickle cell, is a genetic disease where red blood cells can take the shape of a crescent or a sickle, and that change allows them to be more easily destroyed- causing anemia, among other things. Sickle cell disease is caused by defective hemoglobin, which is the oxygen-carrying protein in the red blood cells. Hemoglobin is actually made up of four peptide chains, each bound to a heme group. Different hemoglobins have different combination of these chains. Hemoglobin A (or HbA) – made up of two alpha-globin and two beta-globin peptide chains – is the primary hemoglobin affected in sickle cell. Specifically, the beta-globin chains end up misshapen, and this because of a mutation in the beta-globin gene (or HBB gene). Sickle cell is an autosomal recessive disease, so a mutation in both copies of the beta-globin gene is needed to get the disease. If the person has just one copy of the mutation and one normal HBB gene, then they are a sickle cell carrier – also called sickle cell trait. Having sickle cell trait doesn’t cause health problems, unless the person is exposed to extreme conditions – like high altitude or dehydration – where some sickle cell disease symptoms can crop up. Almost always, the sickle cell mutation is a non-conservative missense mutation, that results in the sixth amino acid of beta-globin being valine instead of glutamic acid. a non-conservative substitution means that the new amino acid – valine, which is hydrophobic – has different properties than the one it replaced – glutamic acid, which is hydrophilic.

Symptoms?

A hemoglobin tetramer with two alpha-globin and two mutated beta-globin proteins is called sickle hemoglobin, or HbS. HbS carries oxygen perfectly well but when its deoxygenated, HbS changes its shape, which allows it to aggregate with other HbS proteins and form long polymers that distort the red blood cell into a crescent shape – a process called sickling. Repeated sickling of the red blood cells damages their cell membranes and promotes premature destruction. Since this happens within the vasculature, its called intravascular hemolysis. This destruction of red blood cells not only leads to anemia, which is the deficiency in red blood cells, but also means a lot of hemoglobin is spilling out. Recycling that heme group yields unconjugated bilirubin, which at high concentration can cause scleral icterus, jaundice, and bilirubin gall stones. To counteract the anemia of sickle cell disease, the bone marrow makes increased number of reticulocytes, which are immature red blood cells. This ends up causing new bone formation and the medullary cavities of the skull can expand outwards, which causes enlarged cheeks and a “hair-on-end” appearance on skull x-ray. Extramedullary Hematopoiesis – which is red blood cell production outside the bone marrow- can also happen-most often in the liver- which can cause hepatomegaly.

In sickle form, red blood cells tend to get stuck in the capillaries -called vaso-occlusion. Starting at infancy, they can clog up blood flow in the bones of the hands and the feet. Later, they get stuck in other bones, causing sickle pain crises. Red blood cells can also clog up the spleen, which can lead to an infract to the spleen, as well as an enormous backup of blood in the spleen, which is a life threating complication.

Diagnosis?

Given all these symptoms, its important to diagnose sickle cell as early as possible. So, its included in the newborn blood spot screen in some countries, and can also be identified with a blood smear looking for sickled cells, or by identifying HbS using protein electrophoresis.

Treatment?

The factors that cause red blood cells to sickle – which are hypoxia, dehydration, and/or acidosis – can all be improved with oxygen and fluids, which are the mainstays of treatment. In addition, opioids are usually used to manage pain, and antibiotics are used to treat and underlying bacterial infections causing acute chest syndrome. Occasionally, blood transfusions are also used, but the risk of multiple transfusions include iron overload and developing immunologic intolerance to foreign blood. Finally, children with sickle cell typically get prophylaxis with penicillin and an additional polysaccharide vaccine against streptococcus pneumoniae to help prevent sepsis and meningitis with encapsulated bacteria. More rarely, bone marrow transplants have been used in some patients; and – given that sickle cell involves a single point mutation – gene therapy is another option that’s being researched. Gene therapy?

Two years ago, a French teen with sickle cell disease underwent a gene therapy treatment intended to help his red blood cells from “sickling.” In a paper published Thursday in the New England Journal of Medicine, the researchers revealed that today, half of his red blood cells have normal-shaped hemoglobin. He has not needed a blood transfusion, which many sickle cell patients receive to reduce complications from the disease, since three months after his treatment. He is also off all medicines.

To reiterate, the paper is a case study of just one patient. Bluebird Bio, the Massachusetts biotech company that sponsored the clinical trial, has treated at least six other trials underway in the US and France, but those results have not yet been fully reported. The gene therapy has not worked quite as well in some of those other patients; researchers say they are adjusting the therapy accordingly. It is also possible that the boy may eventually experience some blood flow blockages again in the future.

The results, though early, are encouraging. They represent the promise of new genetics technologies to address a disease that many people suffered from along the years.