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.

100 comments

  1. I though Howell-Jolly bodies were seen in Spherocytosis? Are they seen in both perhaps? Maybe they're just seen in all abnormal hematopoietic disease idk

  2. Your work is wonderful. Also, seeing this reviewed by Sir Rishi Desai is a huge plus, he is an amazing teacher. Please keep helping people like me all around the world. Thanks loads

  3. The "folate trap" is an interesting aspect of hematology, also. ๐Ÿ™‚ I would greatly appreciate a video of it. ^_^

  4. Thanx for your videos . They actually help me a lot . I watch these before reading the text in my mbbs books. Makes it easier to understand . Plz make videos on thalassemia ,megaloblastic and iron deficiency anemia

  5. Holy shit. Iโ€™m like mind blown how much I just learned and UNDERSTOOD from such a quick video. That was incredible!

  6. Make videos on all types of anemia like pernicious anemia, megaloblastic anemia, folic acid deficiency anemia.

  7. Osmosis is the best medicine channel I have ever seen thanks osmosis team for such wonderful teaching and video

  8. it will be a sin if I not give any compliment to u and ur videos. it tremendously helps me a lot. is there any open/close questions group where I can ask?

  9. Your videos are absolutely fantastic! So informative, comprehensive and INTERESTING. Great job and really appreciated.

  10. I have sickle cell as well and I'm going through a crisis rn hoping to find people who know what I'm going through

  11. Last year I dropped all my medication including hydroxyurea,it wasn't helping, I only manage my sickle cell through diet and positive thoughts and feelings and yoga practice and it has worked great no more crisis pains…how I made this work is by rising through a lot of crisis pains I strengthened my Will and have been able to manifest a life of balance, no stress/dealing with stress/self awareness= no crisis pains

  12. Your videos are perfect. Nevertheless I have a request, please put here some movie about megaloblastic or pernicious anemia. Thank you so much: D

  13. Thalassemia and sickle cell anemia are they the same disease? Im sorry for this lame question, but i need an explanation. Thankyou ๐Ÿ™‚

  14. plz suggest me the hospital name where sickle cell deases may be cure or treat. my daughter suffering from such type of dieses. plz anyone have idea about the hospital plz contact me on my mobile number –9673800330.
    plz plz I request to everyone

  15. I have to do a science project on this but I barely understand what he is saying. Science should be considered a completely different language.

  16. Hey….Plz don't use too many terminologies ๐Ÿ™๐Ÿ™๐Ÿ™๐Ÿ™๐Ÿ™๐Ÿ™
    Video should be understood by everyone..!!!
    Not only to experts

  17. I have been searching for detailed information on this topic for HOURS but most information on it on the internet is just so vague. Thank you for this video, it helped me a lot.

  18. 3/11/19 it looks like scieentists have found a cure for another horrible disease! sicklecell anemia! What's the first thing the patient does after years of research and effort on the part of the scientists?… "thank god" What! You mean thank science!!!

  19. is there also a risk for people with HIV and sickle cel, since it both compromises the immuunsystem and both are prevalent in the same area's of the world?

  20. Hello osmosis? I am 14 years old but my sickle cell does not affect me in any way, Iโ€™ve never had a crisis but Iโ€™m still worried about my future, y am I experiencing no symptoms? Will the symptoms start to appear as I age?

  21. I cannot even begin to explain how much this video has helped me with my final year dissertation. Thank you so much

  22. Very neat and informative…Thank you…!!!เฎตเฎพเฎดเฏเฎ• เฎตเฎณเฎฎเฏเฎŸเฎฉเฏ

  23. Does oxygen actually help the patient? Heard while in theory it should, that it doesn't help with much? Not sure what the criteria for "helping" was (I think pain)

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