Haematology 3
Q. Could you explain the “defect in spectrin” in hereditary spherocytosis—how does this cause cells to become spherocytes?
A. Several mutations have been described in hereditary spherocytosis, each with a slightly different spectrin defect. In all of the mutations, though, there is a problem with the connection between spectrin (a long heterodimer situated just inside the cell membrane) and the cell membrane itself. The cell membrane becomes unstable, and as a result, bits of membrane are lost (but the volume inside the red cell remains intact). When you lose membrane, but keep the cell contents intact, the cell starts to “round up”, and instead of being a biconcave disk, it turns into a ball, or spherocyte. Spherocytes are inherently more fragile than regular old biconcave-disk-shaped red cells. They also are less able to maneuver through tight spaces. So they are more likely to break, causing a hemolytic anemia.
Q. In microangiopathic hemolytic anemia, how does clot formation cause red cells to get “ripped” up? Is it because they have less room to maneuver through the vessel? Also, could you give me an example of an obstetric complication that would cause this anemia?
A. When you form a clot, you start by sticking platelets together, and then through a series of enzymatic steps, you make a long polymer called fibrin that sort of cements the platelets together. Sometimes the fibrin strands (especially if you’re forming a lot of them) can ensnare red blood cells as they are flowing through the vessel. The cells get snagged on the strands of fibrin, and they get ripped apart, forming fragmented red cells (schistocytes) that you can see on a blood smear. This is the mechanism for most cases of microangiopathic hemolytic anemia. However, there are some cases that are due to other mechanisms (one example would be a patient with an old-fashioned, ball-and-socket artificial heart valve that smashes a few red cells every time it closes). These cases are less common, and they really aren’t “microangiopathic” since the problem isn’t really in little vessels. But they’re lumped into the same category because they show fragmented red cells.
In some deliveries, especially difficult or traumatic ones, amniotic fluid can leak into the mother’s blood. Amniotic fluid has procoagulant substances in it that kick off the coagulation cascade (the part of clot formation in which you make fibrin). If you’re making lots of fibrin, chances are the red cells are going to get trapped in the fibrin strands, as described above.
Q. In autoimmune hemolytic anemia, I am confused with the warm and cold types. Does IgG stick better to cells in warm temperatures and IgM in cold? How does agglutination cause anemia? Is it because there are less red cells to circulate freely?
A. Some antibodies tend to stick better to red cells at warm temperatures, and some tend to stick better at cold temperatures. You’re right; for some reason, the antibodies that bind better at warm temperatures tend to be IgG, where as the cold-binding antibodies tend to be IgM.
In cold autoimmune hemolytic anemia, there are two things going on:
1) IgM sticks to the red cells at cold temperatures (like in blood in the fingers and earlobes), where it agglutinates red cells and forms big clumps. This doesn’t cause anemia, and it doesn’t really do much damage – it usually just causes some decreased blood flow to these regions (the agglutination goes away when you warm up those body parts).
2) Complement binds to the red cells (why this happens in cold, but not warm, autoimmune hemolytic anemia, nobody knows). This is bad. Complement pokes holes in the red cells, causing hemolysis. So this is what leads to the anemia – not the agglutination.
In warm autoimmune hemolytic anemia, the anemia is due to macrophages either 1) totally engulfing the IgG-coated red cells (and thus removing them from the circulation), or 2) chewing off bits of membrane (and thus turning the red cell into a spherocytes, which is more fragile than a regular red cell).
Q. Why is LDH increased in hemolytic anemia?
A. Lactate dehydrogenase (LDH) is an enzyme that is present in lots of cells in the body: heart, lung, kidney, liver, muscle, and red blood cells. It’s also present in some tumor cells. Any time these cells are destroyed, LDH is released, and you can measure it in the serum. There are different isozymes (red cells have the LDH-2 isozyme), and you can measure these independently in the serum, so you know where the LDH is coming from.
Practice Questions for Exam #2 (Erythropoiesis, Anemias, Porphyrias and Abnormal Hemaglobin Pigments)
Choose the most correct answer.
| 1. Which of the following is characteristic of pernicious anemia? |
| a) increased production of intrinsic factor |
| b) decreased absorption of vitamin B12 |
| c) antibodies to gastric HCl |
| d) decreased absorption of folate |
| 2. Which of the following deficiencies would most likely lead to megaloblastic anemia? |
| a) vitamin E deficiency |
| b) vitamin B6 deficiency |
| c) iron deficiency |
| d) folic acid deficiency |
| 3. The peripheral blood of a patient with iron deficiency anemia will most likely show what picture? |
| a) microcytic, hypochromic red cells |
| b) microcytic, normochromic red cells |
| c) macrocytic, hypochromic red cells |
| d) normocytic, hypochromic red cells |
| 4. With increased intravascular hemolysis which of the following will likely occur? |
| a) the test for methemalbumin will be negative |
| b) urine hemosiderin will be increased |
| c) unconjugated bilirubin levels will remain normal |
| d) the reticulocyte count will decrease |
| 5. A patient has anemia, decreased RBC indices, and targets on the peripheral smear. Serum iron is normal and electrophoresis shows increased HbF and HbA2. What is a possible diagnosis? |
| a) alpha thalassemia |
| b) sideroblastic anemia |
| c) beta thalassemia |
| d) anemia of chronic disease |
| 6. The anemia in anemia of chronic inflammation (chronic disease) may be caused by which of the following: |
| a) impaired iron metabolism |
| b) autoantibodies |
| c) increased EPO secretion |
| d) increased RBC lifespan |
| 7. Which of the following will likely be seen in the bone marrow in aplastic anemia? |
| a) an M:E ratio of 10:1 |
| b) increased megakaryocyte numbers |
| c) erythroid hyperplasia of the bone marrow |
| d) fatty replacement of the bone marrow |
| 8. During the hepatic stage of hemopoiesis in utero, which globin chains are normally produced in largest quantity? |
| a) zeta and epsilon |
| b) epsilon and gamma |
| c) alpha and beta |
| d) alpha and gamma |
| 9. The absorption of iron from the intestine is primarily regulated by what two factors? |
| a) the amount of iron in the diet and the state of body iron stores |
| b) the amount of erythropoiesis and the level of serum iron |
| c) the state of body iron stores and the amount of erythropoiesis |
| d) the level of erythropoietin and the level of serum iron |
| 10. Which enzyme deficiency is present in congenital erythropoietic porphyria? |
| a) UPG III co-synthase |
| b) ALA synthase |
| c) ferrochelatase |
| d) UPG I synthase |
| 11. The first step in heme synthesis involves which enzyme? |
| a) ALA dehydrase |
| b) ALA synthase |
| c) ferrochelatase |
| d) UPG co-synthase |
| 12. What is the structure of hemoglobin F? |
| a) two alpha chains and two beta chains |
| b) two alpha chains and two delta chains |
| c) two alpha chains and two zeta chains |
| d) two alpha chains and two gamma chains |
Each question is followed by four suggested answers, one or more being correct. Place a check mark in front of each correct answer. All correct answers must be chosen in order to receive marks for the question.
| 13. In sickle cell disease, which hemoglobins will be seen on hemoglobin electrophoresis? |
| ___1) Hemoglobin S |
| ___2) Hemoglobin A |
| ___3) Hemoglobin F |
| ___4) Hemoglobin H |
| 14. A patient's peripheral blood smear shows hypochromic/microcytic RBC. Which of the following anemias might he have? |
| ___1) megaloblastic anemia |
| ___2) sideroblastic anemia |
| ___3) thalassemia |
| ___4) aplastic anemia |
| 15. Which of the following occur during the second stage in the development of iron deficiency anemia? |
| ___1) TIBC increases |
| ___2) serum iron decreases |
| ___3) transferrin saturation decreases |
| ___4) erythropoiesis in the bone marrow becomes affected |
| 16. Which of the following can be found in sideroblastic anemia? |
| ___1) increased M:E ratio |
| ___2) decreased serum iron |
| ___3) increased platelet count |
| ___4) increased ringed sideroblasts |
| 17. Which of the following are intrinsic red cell defects? |
| ___1) hereditary elliptocytosis |
| ___2) Pyruvate Kinase deficiency |
| ___3) Hemoglobin C disease |
| ___4) PNH (paroxysmal nocturnal hemoglobinuria) |
| 18. Which of the following are found in hereditary spherocytosis? |
| ___1) increased polychromasia |
| ___2) increased MCH |
| ___3) decreased M:E ratio |
| ___4) hemolytic anemia |
| 19. Which of the following would be found in hereditary elliptocytosis? |
| ___1) >30% elliptocytes in the peripheral blood |
| ___2) decreased osmotic fragility |
| ___3) normal RBC indices |
| ___4) decreased reticulocyte count |
| 20. Which statements correctly describe the functions of folate? |
| ___1) needed for thymidine nucleotide production |
| ___2) needed as a cofactor for thymidilate synthetase |
| ___3) needed for proper nuclear maturation of hemopoietic cells |
| ___4) needed for proper DNA synthesis |
| 21. Which statements about hemoglobin C are correct? |
| ___1) the basic defect is a substitution of valine for glutamic acid on the beta chain |
| ___2) it forms hexagonal intracellular crystals in RBC |
| ___3) it has decreased oxygen carrying capacity |
| ___4) a hemolytic anemia is seen in the homozygous condition |
| 22. Which of the following are associated with macrocytosis? |
| ___1) folate deficiency |
| ___2) Anemia of chronic disease |
| ___3) increased reticulocyte count |
| ___4) sideroblastic anemia |
| 23. Which of the following statements about sulfhemoglobin are correct? |
| ___1) sulfhemoglobin is ineffective for oxygen transport |
| ___2) sulfhemoglobin can be reversed to oxyhemoglobin in a hyperbaric chamber |
| ___3) sulfhemoglobin results from oxidation of hemoglobin by certain drugs |
| ___4) normal levels are 1-3% (at UAH) |
| 24. Which of the following are associated with microcytosis? |
| ___1) Anemia of chronic disease |
| ___2) G6PD deficiency |
| ___3) B12 deficiency |
| ___4) thalassemia |
A - if the phrase is associated with A only A - hemolytic anemia
Each question consists of a set of four letter headings followed by a list of words or phrases.
In front of each word or phrase, enter the appropriate heading:
B - if the phrase is associated with B only
C - if the phrase is associated with both A and B
D - if the phrase is associated with neither A or B
B - acute post-hemorrhagic anemia
C- both
D- neither
25. ________ ineffective erythropoiesis is evident
26. ________ bilirubinemia is present
27. ________ the red cell count is decreased
28. ________ the reticulocyte count is increased
29. ________ the red cell survival time is decreased
A - paroxysmal nocturnal hemoglobinuria (PNH)
B - paroxysmal cold hemoglobinuria (PCH)
C - both
D - neither
30. ________ an extrinsic hemolytic disorder
31. ________ pancytopenia on the peripheral blood smear
32. ________ deficiency of CD55 and CD59
33. ________ cold autoimmune hemolytic anemia
34. ________ intravascular hemolysis occurs
35. ________ may develop an aplastic bone marrow
ANSWERS
1. b
2. d
3. a
4. b
5. c
6. a
7. d
8. d
9. c
10. a
11. b
12. d
13. #1 and #3
14. #2 and #3
15. #1,#2,#3 and #4
16. #4
17. #1,#2,#3,and #4
18. #1,#3, and #4
19. #1 and #3
20. #1, #2, #3 and #4
21. #2 and #4
22. #1 and #3
23. #1 and #3
24. #1 and #4
25. D
26. A
27. C
28. C
29. A
30. B
31. A
32. A
33. B
34. C
35. A