Hematology: 1:00 - 2:00Scribe: Marjorie O’Neil

Friday, October 23, 2009Proof: Caitlin Cox

Dr. SteciukHemoglobinopathies and ThalassemiasPage1 of 7

Abbreviated Terms: RBC = red blood cell Hgb = Hemoglobin

*The first part of the script is the from Tuesday’s powerpoint:Anemias and Hematopathology. The slide numbers on the script correspond to the updated version of that powerpoint, which is online (there are a few new slides).

  1. Thalassemias [20]:
  2. This is a correction from what he said on Tuesday: the genetic defect is inboth the alpha and beta chains.
  3. Anemia flow chart [27]:
  4. If you have an anemia that is microcytic, it has a low MCV (the cells are small), then your differential diagnosis is often going to be iron deficiency, chronic disease, sideroblastic anemia, and thalassemia.
  5. Differentiating Microcytic Anemias [28]:
  6. This is a list of some lab findings for those disorders. The reason why we have those is so that we can differentiate among these anemias that essentially look the same on a peripheral smear (with the exception of thalassemia which has target cells).
  7. Iron deficiency anemia:
  8. There is decreased storage of iron, and your body is trying to ramp up iron movement around the body so the transferrin (transport protein) is high. The transferrin saturation is decreased.
  9. Sideroblastic anemia:
  10. You have plenty of iron, but the problem is that you’re not able to get iron into Hgb or into the red cell. This results in increased iron stores. Transferrin is actually a little bit decreased, probably because of some inflammation (inflammation causes transferrin to go down, called a negative acute-phase reaction). Because of this the transferrin saturation is up, but you still have a microcytic anemia because you’re not able to effectively get any iron in there.
  11. Anemia of chronic disease:
  12. Transferrin goes down because of inflammation. There is plenty of iron so your ferritin stores are up. The transferrin saturation is decreased.
  13. He said that he doesn’t want us to memorize these but he wanted to summarize it and make it relevant.
  14. Pathophysiological Classification of Anemia [9-11]:
  15. There is decreased production.We talked about most of this and left off at paroxysmal nocturnal hemoglobinuria
  16. There is also increased destruction of red cells that is due to extracorpuscular (or outside the red cell) things such as mechanical destruction, infection, chemical/physical, and antibody mediated destruction of red cells.
  17. In these cases there is nothing wrong with the red cells, but they are being attacked by some outside thing and that is causing the red cell to be destroyed in the circulation and you get hemolytic anemia.
  18. Microangiopathic Hemolytic Anemia [36]:
  19. This is increased destruction (mechanical destruction) of the red cells.
  20. The prototypical disorder associated with this type of anemia is thrombotic thrombocytopenic purpura (TTP). What you see is a thrombocytopenia and hemolytic anemia.
  21. Mechanism: There is a molecule in your blood, Von Willebrand factor (VWF), that is secreted by endothelial cells. It binds to platelets when there is injury to the vessel wall; it helps them stick to the vessel wall whenever there is injury. It is secreted in the form of a long multimer, so there are lots of little pieces of VWF stuck together. Normally in the blood there is a factor called ADAMS-TS13(a metalloproteinase) which cuts the long multimer of VWF into smaller pieces that the platelets can use.
  22. In TTP, there is an absence of ADAMS-TS13 so you get these long multimers in the blood. In the smaller blood vessels (often in the kidney, lungs, or brain), these long forms of VWF get the platelets stuck or trapped in the vasculature causing thrombosis. The red cells try to get through that thrombosis and they are mechanically destroyed.
  23. You get thrombocytopenia (which is a decrease in platelets) because the platelets get used up. You get a hemolytic anemia because the red cells all get destroyed trying to get through that clot.
  24. You diagnose it by the thrombocytopenia, hemolytic anemia, and the ADAMS-TS13 levels.
  25. We treat it with plasma exchange. We basically take out about 70% of someone’s plasma volume and replace it with a donor’s plasma.
  26. Q: How long is the transfusion good for? A:The exchange is not good for very long. You have to continually repeat it. The reason why the ADAMS-TS13 levels go down in these patients is unclear. When you give them normal plasma, with normal levels of ADAMS-TS13 in it, it helps however it is still degraded and goes away. It used to be that TTP had a greater than 90% fatality rate, but with the advent of plasma exchange, there is now only about a 10% fatality rate.
  27. Prosthetic Cardiac Valve [37]:
  28. Another way you can get increased destruction of red cells is if you have a prosthetic cardiac valve. The red cells are mechanically fragmented by the high shear stress of the mechanical cardiac valve.
  29. The prosthetic valve is an example of mechanical destruction. Another example that isn’t listed is one called march hemoglobinuria. When soldiers are marching for long periods of time they get destruction of the red cells in the capillaries in their feet from the continual stomping. They can get blood in their urine and a true anemia.
  30. Infections [38]:
  31. Can cause anemia by increased destruction.
  32. In the picture, the squiggles inside the cell is malaria, (Plasmodium falciparum). Malaria infects and lyses the RBCs, causing a massive anemia. Other things that do this are intracellular: babesia and ehrlichia, or extracellular: clostridium and bartonella. Really anything that goes after the red cell will do it.
  33. Chemical and Physical Agents [39]:
  34. These include: toxins, chemicals, venoms, and burns.
  35. Antibody-Mediated [40]:
  36. Autoimmune hemolytic anemia: older patients, people who are sick, or those who have had transfusions in the past tend to get this. It is production by your body of warm autoantibodies that bind to and cause hemolysis of self-red cells.
  37. Alloimmune hemolytic anemia: something that doctors do to you. The red cells that we transfuse to you, you have natural antibodies to. For example, if you are A then you have natural antibodies to B, and if we transfuse you with B blood, then the antibodies will bind to B and cause a mass hemolytic anemia, which can be fatal.
  38. Drug-induced hemolytic anemia: there are multiple mechanisms that can cause hemolysis, but this is often due to an antibody mediated mechanism. Drugs bind to red cells and antibodies are produced to the red-cell/drug complex—this is called the hapten mechanism, and it causes the red cell to lyse.
  39. Erythrocytosis/Polycythemia [41]:
  40. We will now talk about other disorders in hematopathology that are not anemias.
  41. Erythrocytosis or polycythemia, these are an increase in the number of red cells. This can be caused by non-neoplastic conditions.
  42. Hypoxia:
  43. Your body tries to compensate for hypoxia by increasing the number of red cells.
  44. High affinity Hgb: picks up lots of oxygen in the lungs but it has a high affinity for that oxygen so it doesn’t unload it into your tissues, it mimicshypoxia. Your body responds by trying to increase the amount of Hgb.
  45. Congenital heart malformation: also essentially because of hypoxia and can cause a polycythemia.
  46. Dehydration: this is the opposite of blood loss. If you take away some of the extra water in your blood it will artificially increase the amount of RBCs when we measure them.
  47. Erythropoietin secreting tumor: this will increase the number of RBCs because erythropoietin is what tells the red cells in the bone marrow to differentiate.
  48. Polycythemia vera: this is essentially a precursor cancer of red cells caused by JAK2 mutations (“don’t need to know that”). It is a neoplastic condition that causes the red cells to be increased.
  49. Leukopenia [42]:
  50. A decrease in the number of white cells. The type of white cell matters, so depending on whether you have neutropenia or lymphopenia, you are susceptible to different kinds of organisms. Remember that the white cells are the ones responsible for fighting infection.
  51. Neutropenia: caused by infection, hemodialysis, medication, aplastic anemia, autoimmune, and cyclic neutropenia. Cyclic neutropenia is not very common, but does have dental implications. It presents with recurrent mouth ulcers. Once a month, every 28 days, these patients get neutropenia and get cyclic mouth ulcers. The way you diagnose it is by repeatedly having these patients come in for a CBC and testing their neutrophil count.
  52. Leukopenia: can be caused by infection, heart failure, drugs, malignancy, and HIV (which is the main one; HIV causes a decrease in T cells).
  53. Leukocytosis [43]:
  54. This is an increase in white cells (opposite of leucopenia).
  55. Usually this happens in the context of infection, and it is a healthy response. The white cells fight the infection, so you want more of them when you have an infection. Often this happens in response to strep, cytomegalovirus, infectious mononucleosis, syphilis, hepatitis, vaccination, and drugs.
  56. You can also get a leukocytosis that is neoplastic, due to leukemia.
  57. Thrombocytopenia [44]:
  58. Notice the similarities of this and the anemia slide.
  59. You have impaired production, increased destruction, or a problem with distribution or dilution.
  60. You can get congenital diseases that cause you to have thrombocytopenia, (diseases of impaired production) such as aplastic anemia, vitamin deficiencies (B12 and Folate).
  61. There are a lot of immune mediated ways, decreasing your platelets.
  62. ITP (Immune thrombocytopenic purpura), this is due to autoantibodies; treat this with steroids.
  63. Can get drug-induced production of antibodies; withdraw the drug and the patient gets better. Example of this is heparin induced thrombocytopenia (HIT). After 5 days of exposure to heparin, the patient’s platelet count goes way down; withdraw the heparin and the platelets go back up.
  64. Post-transfusion purpura due to the development of antibodies to platelets.
  65. Non-Immune mediated ways of getting thrombocytopenia:
  66. This happens in pregnancy, pre-eclampsia/eclampsia, HIV, TTP, and also disseminated intravascular coagulation.
  67. Distribution or Dilution:
  68. You can give lots of blood without also giving platelets. If you get a bunch of packed red cells, lots of volume, then your platelet count will go down if you don’t get platelets too.
  69. Thrombocytosis [45]:
  70. This is an increase in platelets. This is most often reactive and can be caused by acute blood loss or surgery. It can happen after a splenectomy because the spleen is responsible for getting rid of the platelets. Can be caused by iron-deficiency anemia, and this is common, you’ll see someone that has a microcytic anemia will also have a thrombocytosis. Inflammation, exercise, and stress can also cause thrombocytosis.
  71. A number of myeloproliferative disorders can cause it too.

**Starting new powerpoint here: Hemoglobinopathies/Thalassemias**

  1. Hemoglobinopathies/Thalassemias[S2]:
  2. We will talk about Hgb basic physiology, hemoglobinopathies (sickle cell disease and hemoglobin C disease are the two most common), and thalassemias (the two major ones are β-thalassemia and α-thalassemia).
  3. Hemoglobin Structure [S3]:
  4. It is composed of four globin chains (round chains). Each of these has one heme group in the center that holds an oxygen. The typical hemoglobin in an adult is composed of two alpha chains and two beta chains (so the typical adult Hgb is α-2 β-2).
  5. In other phases of your life, particularly in the intrauterine phase and right after birth in the neonatal period, there are different Hgb that are at work.
  6. In the early fetal stage, you have epsilon/zeta hemoglobin.
  7. Alpha/gamma is the late fetal or neonatal hemoglobin.
  8. There is also another type, alpha/delta, that is hemoglobin A2 and this is a minor component.
  9. Hemoglobin Structure [S4]:
  10. It has four things that form a circle, 2 alpha and 2 betas. You get 4 hemes. That is the typical adult hemoglobin.
  11. Hemoglobin Molecule [S5]:
  12. This is just another representation of that.
  13. Globin Chains [S6]:
  14. This shows you the different types of hemoglobin in your life. They are different because they are produced by different organs.
  15. In very early fetal life, you have epsilon and zeta, produced predominantly by the yolk sac. As intrauterine life progresses, the liver and spleen produce alpha and gamma. When you are born, alpha/gamma is your predominant hemoglobin (this is called fetal hemoglobin, or Hgb F). Alpha remains for the rest of your life, but after you’re born the gamma starts decreasing and beta starts increasing (bone marrow produces beta, liver produces gamma). By the time you are about 6 months old, most of your hemoglobin is alpha/beta. You also have a small production by the bone marrow of the delta form (A2) and it usually makes about 1-3%.
  16. Normal Hemoglobins [S7]:
  17. Adults (A):
  18. Hgb A1 (22): represents 95-98% of the hemoglobin in normal adults
  19. Hgb A2 (22): 2-3% of the hemoglobin.
  20. Hgb F (22): 0.8-2.0% of the hemoglobin. This is called fetal hemoglobin, but we all have trace amounts of this floating around in our peripheral blood.
  21. Child (HgbF):
  22. Hgb F is 50-80% in the newborn, at 6 months it is down to about 8%, and after 6 months it is down to 1-2%.
  23. Normal Hemoglobin Types [S8-9]:
  24. Hgb A is α2 β2 (alpha 2-beta 2). That is normal adult hemoglobin, and its production increases rapidly after birth. By 6 months, it is the majority of what is in your blood.
  25. Hgb F (fetal hemoglobin) is α2 γ2(alpha 2-gamma 2). You see this during late and mid fetal life and it goes away shortly after birth. HgbF has a higher affinity for oxygen than Hgb A; this is good for the fetus. The mother with Hgb A pumps blood to the placenta. Hgb F has a higher affinity for oxygen than does A, so the oxygen will be transferred from the mother’s Hgb A to the Hgb F allowing the fetus to get oxygen.
  26. Hgb A2 is α2 δ2 (alpha 2-delta 2). You have a little bit of delta chain synthesis starting around birth and continuing throughout life. In the normal adult, there is a small percent, 2-3%, in the peripheral blood.
  27. Hemoglobin Structure/Function [S10]:
  28. This is a review of the sigmoid curve with the right and left shift.
  29. Oxygen transport: the oxygen is bound to the hemegroups. There are 4 heme groups.
  30. The oxygen-hemoglobin curve is sigmoid shaped. In the lung the pO2 is 100%, the hemoglobin is saturated. In the tissue the pO2 is 40 mm and that is about 66% saturation.
  31. There are a variety of things that affect the affinity of oxygen for the hemoglobin causing a right or left shift. These include 2,3 DPG, hydrogen ion (pH), CO2, and ATP. Low affinity hemoglobin causes a right shift, meaning that you’re carrying less oxygen on the hemoglobin, and high affinity hemoglobin means that you’re carrying more oxygen.
  32. O2 Dissociation Curve [S11]:
  33. Skipped.
  34. Chart [S12]:
  35. He says he won’t ask us about this but someone else may.
  36. Shifts to the left are typically caused by decreases: decreased H+ ions, decreased 2,3 DPG (*the chart is incorrect and says BPG. It should read DPG*), and decreased pCO2. One however is an increase: increased oxygen affinity.
  37. Shifts to the right are opposite. They are caused by increases.
  38. Central Dogma of Molecular Biology [S13]:
  39. DNA is transcribed to make RNA. RNA is translated to make protein.
  40. Hemoglobin Genetics [S14]:
  41. The globin structural genes for the beta, gamma, and delta chains are on chromosome 11. For alpha it is on chromosome 16.
  42. In the red cell, mRNA synthesis takes place in nucleus. The mature red cell has no nucleus so mature RBCs lack mRNA. Therefore all of its protein and hemoglobin are made when it is an erythroid precursor or a reticulocyte, a very early red cell.
  43. Gene expression of these hemoglobin chains is codominant meaning that you get one from each parent and you make about half of each. Example: suppose your mom has a mutated beta chain and she gives that gene to you, then you will make half normal chains from your dad and half mutated chains from your mom.
  44. Abnormal Hemoglobins [S15]:
  45. Greater than 350 have been identified.
  46. Understand the two most common hemoglobinopathies, which are Hgb S and Hgb C.
  47. Both of these are caused by a point mutation in the sequence of the beta chain.
  48. Hgb S (sickle cell hemoglobin) has a mutation at the 6th position where a glutamine is turned into a valine. That changes the charge of that area of the hemoglobin molecule causing a conformational change of the shape of the hemoglobin molecule.
  49. Hg C also has a change at the 6th position, but glutamine is turned into a lysine. This causes a different charge change so you get a slightly different change in conformation so you get a different clinical picture.
  50. Hgb S and C are most prevalent in Africa and people of African descent.
  51. Functional Hgb Abnormalities[S16]:
  52. What happens with Hgb S and C? Why are these bad?
  53. The substitutions change the conformation of hemoglobin and this changes the solubility of hemoglobin. When you try and get more hemoglobin into a spot, that hemoglobin tends to precipitate out. There is a lot of hemoglobin in red cells so if you make them less soluble, they will precipitate out and form crystals within the cell.