Thalassemias and Hemoglobinopathies - Weir 03.17.15 Flashcards
Provide 2 examples of Hg disorders - one quantitative and one qualitative.
- Quantitative: thalassemias
- Qualitative: sickle cell
How are B12 deficiency and folate deficiency synergistic?
- B12 and folate deficiency affect the lining of the gut because they affect rapidly dividing cells, so one can cause the other, in some cases
What is the genetic cause of alpha thalassemia? Sickle cell?
- Alpha thalassemia: deletion of alpha genes
- Sickle cell: point mutation in beta gene causing valine substitution for glutamic acid
What is the globin structure of an infant with hydrops fetalis?
- 4 gamma chains
Why is time important when considering decreased production of alpha and beta globin chains?
- Because different globins are more prevalent at different time points post-conception
- Alpha rises quickly, and is always present
- Gamma rises quickly post-conception (to alpha level), but begins to decline rapidly around 36 weeks, and is minimal 6-12 mos after birth
- Beta rises slowly post-conception, but starts to increase rapidly around 36 weeks, rising to a similar level to alpha
What chromosomes are the alpha and beta globin genes on? Describe these genes and their errors in thalassemia.
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Alpha: 16
1. 2 alpha genes on e/chrom, so 4 total -> generally caused by total deletion (thal)
2. Hgb H: alpha thal with all Hgb B (tetramers) - Beta: 11
- 1 beta gene on each chromosome, so 2 total -> can have absent beta globin synthesis, B0, or just reduced (but detectable) synthesis, B+
- Point mutation that decreases beta chain (thal)
What is the cause of hemolysis in beta thalassemia?
Unpaired alpha chains
Describe the different mechanisms of hemolysis in beta thalassemia vs. alpha thalassemia.
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Beta: decreased beta chains, so excess unpaired alpha chains can huddle together, crystalize (inclusion bodies), and damage RBC membrane, even causing flipping (missing flipase) -> INC secondary thrombosis and secondary autoimmune hemolysis
1. Mostly happens in the bone marrow (cell death), and is an erythropoiesis problem - Alpha: beta hemichromes can also form Heinz bodies (membrane-bound precipitates that damage mem), but RBCs tend to make it to bloodstream before they are hemolyzed (hemolytic anemia process)
What is going on here?
- Bone marrow from skull
- In the untransfused pt, there is a striking expansion of hematopoietically active marrow. In bones of the face and skull, burgeoning marrow erodes existing cortical bone and induces new bone formation, giving rise to “crew cut” appearance on x-rays
What are the thalassemia syndromes?
- A heterogeneous group of disorders caused by inherited mutations that decrease synthesis of either alpha- or beta-globin chains that compose adult hemoglobin, HbA (alpha2, beta2)
- Lead to anemia, tissue hypoxia, and red cell hemolysis, related to imbalance in globin chain synthesis
- Image: severe osteoporosis in undertransfused patient
Why are the thalassemias so prevalent?
- As with sickle cell and other common inherited red cell disorders, thought to be due to the protection they afford heterozygous carriers against malaria
- Image: splayed teeth due to widening of maxilla and mandible in thalassemia major
By what two mechanisms do thalassemias cause anemia?
- Cause anemia via: 1) decreased red cell production, and 2) decreased red cell lifespan
- Image: pallor, short stature, wasted limbs, and massive hepatosplenomegaly in undertransfused case of beta thalassemia major
By what two mechanisms does impaired beta globin synthesis result in anemia?
- Two mechanisms:
1. Deficit in HbA syn produces underhemoglobinized hypochromic, microcytic red cells with subnormal O2 transport capacity
2. More important is diminished survival of red cells and their precursors, resulting from imbalance in alpha and beta globin synthesis - Image: major leg ulcer in beta thalassemia major (can occur in all types of hereditary anemias, incl sickle cell and hereditary spherocytosis)
What does this patient have? Describe what you see.
- Beta-thal major: severe anemia w/o transfusions
- Peripheral film: nucleated RBCs, microcytosis, and hypochromasia with morphologic changes: target cells (more common in beta than alpha, but these will be clue on exam), teardrop cells, fragments, basophilic stippling
- Nucleated RBCs may be dysplastic or show abnormal hemoglobinization; neutrophilia, thrombocytosis may also occur
- Howell-Jolly bodies also present here because this pt has had splenectomy for hypersplenism
Why do thal patients get iron overload?
- Transfusion iron (when very young)
- Increased Fe absorption b/c ineffective erythropoiesis
1. Increased EPO = decreased hepcidin -> intestinal absorption and release of iron from macrophages;
A. When transferrin saturated, NTBI circulates, and may be taken up by liver, heart, endocrine cells
A 22 y/o immigrant with shortness of breath and swollen neck veins and thalassemia comes into your office. What do you think is going on?
- Heart failure
- May also see hemochromatosis and liver damage or failure
- Hepcidin turned off (due to upregulation of EPO in beta thal)
What do you think is going on in this liver biopsy? What dx are you thinking?
- Beta thalassemia major
- Normal architecture, with fibrosis in portal triads and nodular regeneration of hepatic parenchymal cells
- Sclerosis with iron deposition (blue = iron) in hepatic parenchymal cells, bile duct epithelium, macros, and fibroblasts
What is going on here? This can be a result of which hemoglobinopathy?
- 27 y/o male with: hepatocellular carcinoma on the left, and hepatic cirrhosis on right (and hepatitis C infection)
- Both of these can arise as a consequence of beta thal major
Memorize this chart. Please and thank you.
- REMEMBER: problem in beta thalassemia not too few betas, but rather too many unpaired alphas
What are your tools for diagnosing thalassemia? Which one is shown here? Descibe how it is used to dx alpha thal.
- Family history, CBC, blood smear, physical exam
- Beta thal: elevated A2 or fetal Hgb (electrophoresis)
-
Alpha thal: high performance liquid chromatogrpahy (HPLC) shown here -> more accurate at quantifying and separating Hgb A2 than is Hgb electrophoresis
1. Disproportionately elevated RBC as compared to Hgb, very low MCV with normal ferritin
2. PCR (known mutation)
3. Restriction Fragment Length Polymorphism Analysis (unknown mutation) –> rarely do this
Memorize this one too. What is the main goal of thal treatment? What is a possible cure?
- Main thing to do is keep the iron down and blood up
- Allogeneic bone marrow transplants possible cure, and works esp. well in young people with matched donor: Dr. Weir showed results of trial with relatively high survival rates (>80%) and low mortality rates (<15%)
What do you think happened here? What are the cause and mechanism?
- Hydrops fetalis from Hgb Bart disease
- Loss of all four alpha-globin genes results in severe anemia, high-output heart failure, splenomegaly, edema, and intrauterine or immediately post-partum death for the affected fetus
- Dystocia (obstructed labor), eclampsia (onset of seizures in woman with preeclampsia: HTN, elevated HR, and protein in urine), and hemorrhage can occur in mother carrying the affected fetus
What do you see here? Why?
- HbH inclusions: precipitated beta globin tetramers
- RBC near the top central area (red arrow) shows many inclusions in evenly diffuse distribution, creating “golf ball” pattern -> distinct from the reticulocytes with uneven reticulin deposits (black arrows)
- NOTE: these inclusions are rare in alpha thal trait (1 deletion) or 2-gene deletion, but frequent with HbH; Heinz bodies would be larger and not so numerous, and Howell-Jolly bodies are usually singular inclusions
What is the significance of the genetic variation shown here?
- Alpha thals caused by inherited deletions that result in reduced or absent syn of alpha-globin chains -> severity depends on how many alpha-globin genes are affected
What does this blood smear demonstrate? Is this alpha or beta thal?
- This is HgH disease: microcytosis, hypochromasia, and numerous morphologic abnormalities, incl target cells, microspherocytes, and fragments
- Basophilic stippling may occur, and polychromasia is present
- You can’t tell the difference between alpha and beta thal from this image, although you can tell this is a thal (i.e., you would not be able to dx it as HgH either without additional info)
Briefly describe the sickle hemaglobinopathy epi.
- 8% of AA have the gene
- 1/625 homozygous
- Mediterranean, Saudi Arabia, India
Note how awesome this image is.
Good job!
How is sickle cell involved in vaso-occlusive crisis?
- SS-RBCs, other inflammatory mediators induce the activation of the endothelium -> damaged, stimulated endothelium poised to recruit leukocytes
- E-selectin on endo crucial for generating a secondary wave of activating signals -> polarized expression of activated αMβ2 integrin (Mac-1) at leading edge of the crawling neutrophil, allowing the capture of circulating discoid and sickle-shaped erythrocytes
- Culminates in VOC in postcapillary venules -> not just due to sickle cells plugging things up, but also inflam from white cells and depleted NO, which may cause vascular spasm
What do you see here?
- Sickle cell anemia
- Sickle, hypochromic, and target cells
What is going on in these two images?
- Sickle cell anemia
- Painful, swollen fingers (dactylitis) on left
- Marked shortening of middle finger on the right due to dactylitis in childhood affecting growth of epiphysis
What do you see here?
- Sickle cell anemia
- Radiograph of pelvis shows avascular necrosis with flattening of femoral heads -> more marked on the right
- Coarsening of the bone architecture, and cystic areas in the right femoral neck caused by previous infarcts
What complication of sickle cell is shown here? Explain.
- Acute chest syndrome due to embolization of fat from infarcted bone
- High-power view of lung showing alveolar edema, fat embolism in arteriole surrounded by sickle cells, and microthrombi in alveolar capillaries
What is going on here? What hemoglobinopathy might it be associated with?
- Necrosis and ulceration
- Could be a result of sickle cell anemia or thalassemia (also can be associated with several types of hereditary hemolytic disorders, e.g., hereditary spherocytosis)
What is this? Make sure you understand it, and how to read it if you were given a normal ID at the top.
- Sickle cell anemia hemoglobin electrophoresis
- Agar separation usually used to distinguish these
- Uppermost lane shows raised Hb A2 level of beta-thal trait
What are these? Make sure you know how to interpret them (if given a normal).
A. Hemoglobin electrophoresis patterns in the types of patients indicated
B. High performance liquid chromatography: the different hemoglobins elute at different times from the column and their concentrations are read automatically
- In this example, the patient is a carrier of sickle cell disease
- NOTE: things are often much more complex than this (class examples of mixed sickle cell and thalassemia -> compound heterozygosity IS A THING)
What do you see here in A? B? Describe the cells and diagnose.
A. Sickle cell anemia: deeply staining sickle cells, target cells, and polychromasia
B. Homozygous Hb C disease (mild hemolytic anemia due to substitution in beta globin chain: glu to lys): many target cells, deep staining rhomboidal, spherocytic cells -> more blunt crystals and increased density
