Sickle cell anemia – causes, symptoms, diagnosis, treatment & pathology

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 red blood cells. Hemoglobin is actually made up of four peptide chains, each bound to a heme group. Different hemoglobins have different combinations 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 is 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 trait. Having sickle trait doesn’t cause health problems, unless the person is exposed to extreme conditions –like high altitude or dehydration– where some sickle cell disease-like symptoms can crop up. What it does do is decrease the severity of infection by Plasmodium falciparum malaria. So in parts of the world with a high malaria burden, like Africa and pockets of Southern Asia, those with sickle trait actually have an evolutionary advantage. This phenomenon is called heterozygote advantage; and its unfortunate consequence is a high rate of sickle cell disease in people from those parts of the world. 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. 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 it is 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. Conditions favorable for sickling include acidosis –which decreases hemoglobin’s affinity for oxygen– and small, low-flow vessels –where red blood cells’ hemoglobin molecules have plenty of time to dump lots of oxygen molecules. Repeated sickling of red blood cells damages their cell membranes and promotes premature destruction. Since this happens within the vasculature, it’s called intravascular hemolysis. This destruction of red blood cells not only leads to anemia, which is a deficiency in red blood cells, but also means a lot of hemoglobin spilling out. Free hemoglobin in the plasma is bound by a molecule called haptoglobin and gets recycled, which is why a low haptoglobin level is a sign of intravascular hemolysis. Recycling of 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 numbers of reticulocytes, which are immature red blood cells. This ends up causing new bone formation and the medullary cavites of the skull can expand outward, 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 in infancy, they can clog up blood flow in the bones of the hands and the feet –called dactylitis, or swelling and pain of the digits. Later, they get stuck in other bones, causing sickle cell pain crises or avascular necrosis of the bone. Red blood cells can also clog up the spleen, which can lead to an infarct to the spleen, as well as an enormous backup of blood in the spleen –called splenic sequestration, a life-threatening complication. Over time, splenic infarcts can lead to an auto-splenectomy –where the spleen scars down and fibroses to basically nothing. Having an absent or non-functional spleen means a person is susceptible to encapsulated bacteria –like Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Salmonella species– since encapsulated bacteria are normally opsonized and then phagocytized by macrophages in the spleen. It also leaves a person with Howell-Jolly bodies –basophilic nuclear remnants in red blood cells which can be seen on a peripheral blood smear. Sickled red blood cells can also get stuck in the cerebral vasculature, causing strokes and Moya-moya disease –which is named for “puff-of-smoke”-like collateral vessels that bypass blocked arteries. They can also get stuck in the blood vessels of the lungs, leading to acute chest syndrome. And this is particularly dangerous because it sets up a vicious cycle of congested, deoxygenated red blood cells preventing other red blood cells from getting oxygen. And this is made worse by the lungs’ natural tendency for hypoxic vasoconstriction –which is blood vessel constriction in areas of the lungs that are low in oxygen. In addition, clogging in the renal papillae can cause necrosis, which can manifest as hematuria and proteinuria –blood and protein spilling out into the urine. And in men, clogging of the vasculature of the penis can cause priapism –a painful and prolonged erection. Given all these symptoms, it’s important to diagnose sickle cell as early as possible. So it’s 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. 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 any 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. Another preventative medicine is hydroxyurea –which works by increasing the amount of gamma-globin– which results in more fetal hemoglobin, or HbF. Fetal hemoglobin is made up of two alpha- and two gamma-globin chains, so it doesn’t include the mutated beta-globins. Since it can’t polymerize, it gets in the way of HbS polymers’ being made and prevents sickling. HbF is the primary hemoglobin at birth –which explains why sickle cell symptoms don’t happen until a few months of life, when adult hemoglobin starts to predominate (which contains the mutated beta-globin). 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. All right! As a quick recap: Sickle cell disease is an autosomal recessive genetic disease where the beta-globin subunit of hemoglobin is misshapen, which causes red blood cells to sickle when deoxygenated. And this leads to their premature destruction as well as vaso-occlusion. Thanks for watching. You can help support us by donating on Patreon, subscribing to our channel, or telling your friends about us on social media.


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