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305 Cards in this Set
- Front
- Back
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What are the types of RBC disorders?
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- Anemias (↓ RBC mass)
- Polycythemia (↑ RBCs, aka erythrocytosis) |
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What is the definition of anemia?
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Reduction in O2- transporting capacity of blood, usually stems from a decrease in RBC mass to subnormal levels
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How can you classify the anemias based on cause?
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- Bleeding (hemorrhage)
- ↑ RBC destruction - ↓ RBC production |
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What is an example of a RBC disorder that overlaps in the categories that cause the anemia?
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Thalassemia - caused by ↓ RBC production and early destruction
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What kind of compensatory mechanism do most anemias cause? What are the exceptions?
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- ↓ in tissue O2 tension triggers increased production of erythropoietin from kidney
- Exceptions: chronic renal failure and chronic inflammation |
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What are the effects of the compensatory increase in epo in anemia?
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- Compensatory hyperplasia of erythroid precursors in BM
- In severe anemias, drives appearance of extramedullary hematopoiesis within secondary organs (liver, spleen, lymph nodes) |
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What does the term "hemolysis" mean?
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RBC destruction
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What are the impacts of compensatory increase in epo in anemias caused by acute bleeding or increased RBC destruction (hemolysis)?
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- Increases production of RBCs 5-8x
- Leads to ↑ appearance of Reticulocytes in PB |
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What are the impacts of compensatory increase in epo in anemias caused by decreased RBC production (aregenerative anemias)?
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Subnormal reticulocyte counts (reticulocytopenia)
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What characteristics can you use to classify RBC anemias, based on morphology?
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- Size
- Color - Shape |
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What are the morphological changes that can occur in anemia and what do they suggest about the cause?
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- Microcytic (small RBCs): iron deficiency, thalassemia
- Macrocytic (large RBCs): folate or vitamin B12 deficiency - Normocytic but w/ abnormal shapes: hereditary spherocytosis, sickle cell disease |
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What are the indices used to evaluate RBCs?
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- Mean Cell Volume (MCV)
- Mean Cell Hemoglobin (MCH) - Mean Cell Hemoglobin Concentration (MCHC) - Red Cell Distribution Width (RDW) |
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What does MCV stand for? What does it measure? Units?
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Mean Cell Volume:
- Average volume per RBC - Expressed in femtoliters (cubic microns) |
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What does MCH stand for? What does it measure? Units?
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Mean Cell Hemoglobin:
- Average mass of hemoglobin per RBC - Expressed in picograms |
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What does MCHC stand for? What does it measure? Units?
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Mean Cell Hemoglobin Concentration:
- Average conc. of hemoglobin in a given volume of packed RBCs - Expressed in g/dL |
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What does RDW stand for? What does it measure?
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Red Cell Distribution Width:
- Coefficient of variation of RBC volume |
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What are the units for the indices used to evaluate RBCs?
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- MCV: femtoliters (cubic microns)
- MCH: picograms - MCHC: g/dL - RDW: unitless |
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How do you measure the RBC indices?
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Directly measured or automatically calculated by specialized instruments in clinical laboratories
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What lab test can distinguish between hemolytic (↑ RBC destruction) and aregenerative anemias (↓ RBC production)?
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Reticulocyte Count:
- Hemolytic: ↑ Reticulocytes - Aregenerative: ↓ Reticulocytes (directly measured or automatically calculated by specialized instruments) |
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What blood tests / labs can be done to determine the type of anemia?
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- Iron indices
- Plasma unconjugated bilirubin, haptoglobin, and lactate dehydrogenase levels - Serum and RBC folate and vitamin B12 concentrations - Hemoglobin electrophoresis - Coombs test |
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What is evaluated by "iron indices"? What can it tell you?
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- Serum iron
- Serum iron-binding capacity - Transferrin saturation - Serum ferritin concentrations Help distinguish among anemias caused by iron deficiency, chronic disease, and thalassemias |
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What can evaluating "plasma unconjugated bilirubin, haptoglobin, and lactate dehydrogenase levels" tell you?
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These values are abnormal in hemolytic anemias
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What can evaluating "serum and RBC folate and vitamin B12 concentrations" tell you?
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These values are low in megaloblastic anemias
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What is "hemoglobin electrophoresis" used for?
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Used to detect abnormal hemoglobins
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What is "Coombs test" used for?
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Used to detect antibodies or complement on RBCs in suspected cases of immunohemolytic anemia
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When is just assessing the peripheral blood adequate for determining the cause of anemia?
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When it is an isolated anemia (no thrombocytopenia or granulocytopenia)
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When do you need to assess the bone marrow in addition to the peripheral blood for determining the cause of anemia?
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- When the anemia is in conjunction with thrombocytopenia and/or granulocytopenia
- In these cases it is more likely to be associated w/ marrow aplasia or infiltration |
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What determines the clinical consequences of anemia?
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- Severity
- Rapidity of onset - Underlying pathologic mechanism |
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What does it tell you if the onset of anemia is "slow"?
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Deficit in O2-carrying capacity is partially compensated for by adaptations
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What adaptations can compensate for the O2-carrying capacity in slow onset anemias?
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- ↑ Plasma volume
- ↑ Cardiac output - ↑ Respiratory rate - ↑ 2,3-Diphosphateglycerate |
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What is the effect of 2,3-Diphosphateglycerate?
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Glycolytic pathway intermediate that enhances release of O2 from hemoglobin
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In what situations are patients unable to effectively compensate for their anemia with these mechanisms?
- ↑ Plasma volume - ↑ Cardiac output - ↑ Respiratory rate - ↑ 2,3-Diphosphateglycerate |
In patients with compromised pulmonary or cardiac function
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What are the acute clinical manifestations of anemia?
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- Shortness of breath
- Organ failure - Shock |
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What are the chronic clinical manifestations that are common to all types of anemia?
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- Pallor
- Fatigue - Lassitude (lack of energy) |
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What are the clinical manifestations specific to hemolytic anemias?
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Related to increases in turnover of hemoglobin:
- Hyperbilirubinemia - Jaundice - Pigment gallstones |
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What are the clinical manifestations specific to anemias that stem from ineffective hematopoiesis?
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- Inappropriate increases in iron absorption from gut
- Can lead to iron overload (secondary hemochromatosis) - Consequentially leads to endocrine organ and heart damage |
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What are the clinical manifestations specific to severe congenital anemias (eg, β-thallassemia major)?
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- Growth retardation
- Skeletal abnormalities (d/t reactive marrow hyperplasia) - Cachexia (weakness and wasting away) |
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What is the concern when a patient loses >20% of their blood volume acutely?
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- Immediate threat is hypovolemic shock
- If they survive, hemodilution can lead to anemia |
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How does a person compensate to an acute blood loss of >20%?
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- Hemodilution begins at once and reaches full effect within 2-3 days
- Compensatory rise in epo stimulates increased RBC production and reticulocytosis within 5-7 days |
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What kind of anemia accompanies acute blood loss?
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Normocytic and normochromic anemia
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What happens when a patient has chronic blood loss?
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- Iron stores are gradually depleted
- Iron is essential for hemoglobin synthesis and erythropoiesis - Deficiency of iron leads to chronic anemia of underproduction |
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What kind of anemia accompanies chronic blood loss?
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Chronic anemia of underproduction
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What is the normal lifespan of a RBC? What is it called when this lifespan is shorter than usual?
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- 120 days
- Hemolytic anemias: accelerated RBC destruction |
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What can cause Hemolytic Anemias? What is the more common mode of RBC destruction?
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Accelerated destruction of RBCs:
- Intrinsic (intracorpuscular) RBC defects - usually inherited - Extrinsic (extracorpuscular) RBC defects - usually acquired (more common) |
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What are the types of intrinsic (intracorpuscular) RBC defects that cause hemolytic anemia?
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Hereditary:
- Membrane abnormalities - Enzyme deficiencies - Disorders of hemoglobin synthesis Acquired: - Membrane defect (paroxysmal nocturnal hemoglobinuria) |
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What hereditary membrane abnormalities can lead to an intrinsic RBC defect and hemolytic anemia?
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Defects in membrane skeleton:
- Spherocytosis - Elliptocytosis Defects in membrane lipids: - Abetalipoproteinemia |
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What hereditary enzyme deficiencies can lead to an intrinsic RBC defect and hemolytic anemia?
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Enzymes of hexose monophosphate shunt:
- Glucose-6-Phosphate dehydrogenase - Glutathione synthetase Glycolytic Enzymes: - Pyruvate kinase - Hexokinase |
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What hereditary disorders of hemoglobin synthesis can lead to an intrinsic RBC defect and hemolytic anemia?
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Structurally abnormal globin synthesis (hemoglobinopathies):
- Sickle Cell Anemia - Unstable hemoglobins Deficient globulin synthesis: - Thalassemia syndromes |
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What acquired membrane defect can lead to an intrinsic RBC defect and hemolytic anemia?
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Paroxysmal nocturnal hemoglobinuria
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What are the types of extrinsic (extracorpuscular) RBC defects that cause hemolytic anemia?
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- Antibody-mediated
- Mechanical trauma to RBCs - Infections |
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What antibody-mediated defect can lead to an extrinsic RBC defect and hemolytic anemia?
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Isohemagglutinins:
- Transfusion reactions - Immune hydrops (Rh disease of the newborn) Auto-antibodies: - Idipathic (primary) - Drug associated - Systemic Lupus Erythematosus |
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What mechanical trauma to the RBC can lead to an extrinsic RBC defect and hemolytic anemia?
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Microangiopathic hemolytic anemias:
- Thrombotic thrombocytopenic purpura - Disseminated intravascular coagulation Defective cardiac valves |
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What infections can lead to an extrinsic RBC defect and hemolytic anemia?
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Malaria
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What are the features shared by all uncomplicated hemolytic anemias?
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- Decreased RBC life span
- Compensatory increase in erythropoiesis - Retention of products of degraded RBCs (including iron) |
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What is the significance of retention of products of degraded RBCs in uncomplicated hemolytic anemias?
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- Save iron from degraded RBCs
- Because iron is recovered efficiently, RBC regeneration may almost keep pace w/ the hemolysis |
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What are the features of hemolytic anemias in the BM? in the PB?
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- BM: erythroid hyperplasia
- PB: ↑ reticulocytes |
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In severe hemolytic anemias, where does hematopoiesis take place?
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- BM (as always)
- Also in extra-medullary locations (liver, spleen, and lymph nodes) |
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Where can RBC destruction take place?
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- Vascular compartment (intravascular hemolysis)
- Tissue macrophages (extravascular hemolysis) |
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What can cause intravascular hemolysis (in the vascular component) in hemolytic anemia?
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- Mechanical forces (eg, turbulence caused by a defective heart valve)
- Biochemical or physical agents that damage the RBC membrane (eg, fixation of complement, exposure to clostridial toxins, or heat) |
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What are the implications of intravascular hemolysis (in the vascular component) in hemolytic anemia?
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- Hemoglobinemia
- Hemoglobinuria - Hemosiderinuria - Acute tubular necrosis - Unconjugated hyper-bilirubinemia and jaundice |
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What is Haptoglobin?
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- Circulating protein that binds and clears free hemoglobin
- Normally found in plasma |
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What happens to Haptoglobin in hemolytic anemia (intravascular and extravascular causes)?
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Completely depleted from the plasma
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What happens to Lactate Dehydrogenase in hemolytic anemia (intravascular and extravascular causes)?
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Unusually high levels of LDH in plasma
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Where does extravascular hemolysis usually take place? Why does this make sense?
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Within spleen and liver - these organs contain large numbers of macrophages, the principal cells responsible for removal of damaged or immunologically targeted RBCs from circulation
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What is necessary for the RBCs to navigate through the sinuses of the spleen? Implications?
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- It needs to be able to alter its shape
- RBCs with reduced deformability → splenic sequesteration and phagocytosis |
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What are the implications of extravascular hemolysis (not in the vascular component) in hemolytic anemia?
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- Jaundice
- Bilirubin-rich gallstones / pigment stones (if long-standing) - ↓ Haptoglobin in plasma - ↑ LDH (lactate dehydrogenase) in plasma - Reactive hyperplasia of mononuclear phagocytes → splenomegaly |
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What happens in Hereditary Spherocytosis? How is it inherited?
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- Intrinsic defect in RBC membrane → spherocytes
- Non-deformable cells highly vulnerable to sequestration and destruction in spleen - Usually autosomal dominant, but there is a more severe, recessive form in a minority of patients |
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What membrane abnormalities cause Hereditary Spherocytosis?
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Mutations involve Ankyrin, Band 3, and Spectrin
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What are the implications of mutations in Ankyrin, Band 3, and/or Spectrin?
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- Leads to Hereditary Spherocytosis = spherical RBCs
- These mutations weaken the vertical interactions between the membrane skeleton and the intrinsic membrane proteins - Leads to ↓ surface area to volume ratio |
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How do RBCs in Hereditary Spherocytosis get destroyed?
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- Spherocytes have limited deformability and are sequestered in splenic cords
- There they are destroyed by the plentiful resident macrophages |
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How can you treat Hereditary Spherocytosis? Effect?
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- No specific treatment
- Splenectomy - although the RBC defect and spherocytes persist, the anemia (destruction of RBCs) is corrected, however at risk for infections - Partial Splenectomy is gaining favor for hematologic improvement but maintaining protection against sepsis |
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What do spherocytes look like?
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- Dark red
- Lack central pallor |
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What happens to the BM in Hereditary Spherocytosis? PB?
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- BM: compensatory hyperplasia of RBC progenitors
- PB: reticulocytosis (d/t ↑ RBC production) |
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Splenomegaly is more common and prominent in which type of hemolytic anemia? Why? How large?
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- Hereditary Spherocytosis
- Caused by marked congestion of splenic cords and increased numbers of tissue macrophages - 500-1000g |
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What happens to the gallbladder in Hereditary Spherocytosis?
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Cholelithiasis = formation of gallstones (40-50%)
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What are the characteristic clinical features of Hereditary Spherocytosis?
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- Anemia (subclinical to profound, but usually moderate)
- Splenomegaly - Jaundice |
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What feature can help you to diagnose Hereditary Spherocytosis?
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Because of the spherical shape, they have increased osmotic fragility when placed in HYPOTONIC salt solutions
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What infection can cause aplastic crises in patients with Hereditary Spherocytosis? What does it do?
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- Parvovirus B19
- Infects and destroys erythroblasts in the BM - Triggers severe aplastic crises - a lack of RBC production for even a few days results in a rapid worsening of anemia |
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What is the clinical course of Hereditary Spherocytosis?
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- Usually stable
- May be punctuated by aplastic crises - Most severe crises triggered by Parvovirus B19, self-limited |
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What may be necessary for a Hereditary Spherocytosis patient with a severe aplastic crisis triggered by Parvovirus B19?
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May need a supportive blood transfusion during periods of RBC aplasia
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What are hemoglobinopathies? What kind of anemia are they classified as?
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- Group of hereditary disorders caused by inherited mutations that lead to a structural abnormality in hemoglobin
- Hemolytic anemia |
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What is the most common hemoglobinopathy? Mutation?
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Sickle Cell Anemia - valine substitution for glutamic acid at 6th residue in β-globin gene, creates sickle hemoglobin (HbS)
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Normally, what kinds of hemoglobin does an adult have? How frequent? Genes?
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- 96% HbA1 (α2β2)
- 3% HbA2 (α2δ2) - 1% Fetal HbF (α2γ2) |
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What kinds of hemoglobin do homozygotes have? Heterozygotes?
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- Homozygotes: all HbA is replaced by HbS
- Heterozygotes: 50% of HbA is replaced by HbS |
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What is the most common familial hemolytic anemia in the world? How common in Africa? US?
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Sickle Cell Anemia
- In some parts of Africa where malaria is endemic, gene frequency approaches 30% - In US, 8% of African Americans are heterozygotes for HbS, and about 1 in 600 have sickle cell anemia |
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Why is there increased incidence of the sickle cell gene in Africa?
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Protective effect of HbS against Plasmodium falciparum malaria
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Why mediates the sickled shape of RBCs in Sickle Cell Anemia?
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- On deoxygenation, HbS molecules polymerize by interactions of valine residues at position 6
- Polymers distort RBC into elongated, crescentic or sickle shape - Initially reversible upon reoxygenation - Distortion of membrane leads to influx of Ca2+ which causes a loss of K+ and H20, ultimately damaging the membrane skeleton - This cumulative damage leads to irreversibly sickled cells |
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What happens to the irreversible sickled cells in Sickle Cell Anemia?
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Rapidly hemolyzed
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What variables influence the sickling of RBCs in vivo?
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- Presence of hemoglobins other than HbS
- Intracellular concentrations of HbS - Transit time for RBCs through the microvasculature |
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Is there sickling in heterozygous Sickle Cell Anemia? Why or why not?
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No, RBCs have little tendency to sickle because the presence of HbA greatly retards the polymerization of HbS
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What is it called if you are heterozygous for Sickle Cell Anemia?
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You are said to have "Sickle Cell Trait"
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What happens in HbC? How common?
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- Mutant β-globin
- Lysine residue instead of glutamic acid at position 6 - 2.3% of African Americans are heterozygous carriers of HbC - 1 in 1250 newborns are compound heterozygotes of HbC and HbS |
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What happens if you have HbC and HbS?
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HbSC disease:
- HbC has a greater tendency to aggregate with HbS than HbA - Symptomatic sickling disorder |
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How does Sickle Cell Anemia affect infants
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- Infants have HbF until around 5-6 months
- HbF interacts weakly with HbS, so newborns do not manifest the disease until HbF falls to adult levels |
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How does intracellular concentration of HbS affect sickling? How is this relevant to their symptoms?
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Polymerization is concentration dependent:
- RBC dehydration → ↑Hb concentration → facilitates sickling - Co-existance of α-thalassemia → ↓Hb concentration → reduces sickling - In heterozygotes, they have low HbS concentration, so reduced sickling |
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How does RBC dehydration affect a patient with Sickle Cell Anemia?
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This facilitates sickling because the effective concentration of HbS is increased
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How does the co-existance of α-thalassemia affect a patient with Sickle Cell Anemia?
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α-Thalassemia decreases Hb concentration and reduces sickling
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How does the transit time for RBCs through microvasculature affect patients with Sickle Cell Anemia?
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- Normal transit time of RBCs is too short for significant polymerization of deoxygenated HbS
- Sickling in microvasculature beds is confined to areas w/ sluggish blood flow |
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Which areas of the body have sluggish blood flow and increase the risk for sickling in patients with Sickle Cell Anemia?
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- Spleen and Bone Marrow
- In other microvasculature beds by acquired factors that retard the passage of RBCs |
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What can slow the flow of blood? Implications?
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Inflammation:
- ↑ Adhesion of leukocytes and RBCs to endotheium - Induces exudation of fluid through leaky vessels *This leads to increased risk of sickling |
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How do sickled RBCs interact with the endothelial cells compared to normal?
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- Sickled RBCs have an increased tendency to adhere to endothelial cells
- Probably because bouts of sickling causes membrane damage that makes them "sticky" |
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What are two major consequences of RBC sickling?
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- Chronic Hemolytic Anemia - mean life span of RBCs is only 20 days (1/6 of normal)
- Microvascular Obstructions - widespread, resulting in ischemic tissue damage and pain crises |
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How does vaso-occlusion relate to the number of irreversibly sickled cells?
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- Vaso-occlusion does NOT correlate w/ number of irreversibly sickled cells
- May result from factors such as infection, inflammation, dehydration, and acidosis, that enhance the sickling of reversibly sickled cells |
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What do the anatomic alterations in Sickle Cell Anemia stem from?
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- Severe chronic hemolytic anemia
- Increased breakdown of heme to bilirubin - Microvascular obstructions (provokes tissue ischemia and infarction) |
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What happens to the organs in Sickle Cell Anemia? Cause?
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- Heart, liver, and renal tubules show signs of hypoxia-induced fatty changes d/t anemia and vascular stasis
- Vascular congestion, thrombosis, and infarction can affect any organ, including bone, liver, kidneys, retinas, brain, lungs, and skin - Priapism - penile fibrosis and erectile dysfunction - Hemosiderosis (iron overload) - Gallstones |
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What happens to the BM and other lymph organs in Sickle Cell Anemia?
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- BM: compensatory hyperplasia of erythroid progenitors, also prone to ischemia because of sluggish blood flow and high rate of metabolism
- Extramedullary hematopoiesis may appear in liver and spleen |
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What happens to bone in Sickle Cell Anemia?
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- Cellular proliferation in bone causes bone resorption and secondary new bone formation
- Results in prominent cheekbones and changes in skull resembling a "crewcut" in radiographs |
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What happens to the spleen in Sickle Cell Anemia?
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- Splenomegaly (up to 500g) d/t red pulp congestion d/t entrapment of sickled red cells in children
- Chronic splenic erythrostasis produces hypoxic damage and infaracts → Autosplenectomy by adulthood (reduced to useless nubbin of fibrous tissue) |
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How severe is the anemia in Sickle Cell Anemia? Average hematocrit?
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- Moderate to severe anemia
- 18-30% hematocrit (normal is 36-48%) |
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What is the clinical course of Sickle Cell Anemia?
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- Unremitting course
- Punctuated by sudden vaso-occlusive crises and aplastic crises |
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What is the most serious type of crises in Sickle Cell Anemia? Location?
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Vaso-occlusive or pain crises - commonly involve bone marrow
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What are the feared complications of Sickle Cell Anemia? Causes? Implications?
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Acute Chest Syndrome
- Triggered by pulmonary infections or fat emboli from infarcted marrow Stroke - Damage by vaso-occlusive crises in brain All organs can be affected, but acute chest syndrome and stroke are the two leading causes of ischemia-related death |
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What happens in Acute Chest Syndrome?
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- Triggered by pulmonary infections or fat emboli from infarcted marrow
- Blood flow in inflamed, ischemic lung becomes sluggish and spleen-like, leading to sickling within hypoxemic pulmonary beds - Exacerbates the underlying pulmonary dysfunction, creating vicious circle of worsening pulmonary and systemic hypoxemia, sickling, and vaso-occlusion |
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What happens in aplastic crises in Sickle Cell Anemia?
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- Sudden decrease in RBC production
- Usually triggered by Parvovirus B19 - Severe and self-limited |
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Why are patients with Sickle Cell Anemia prone to infections?
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- As children, the sickled RBCs cause splenomegaly and interfere w/ bacterial sequestration and killing
- As adults, the spleen goes through auto-infarction so they are functionally asplenic and susceptible to infection |
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Patients with Sickle Cell Anemia are predisposed to what kinds of infections?
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- Encapsulated bacteria, such as pneumococci
- Fatal septicemia - Salmonella osteomyelitis (possibly d/t acquired defects in complement function) |
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How do you diagnose Sickle Cell Anemia, Sickle Cell Trait, and Prenatal Sickle Cell Anemia?
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Homozygous:
- Irreversibly sickled RBCs on PB smear Heterozygous / Sickle Cell Trait: - Sickling can be induced in vitro by exposing cells to marked hypoxia - Confirmed by electrophoretic demonstration of HbS Prenatal: - Analyze fetal DNA obtained by amniocentesis or biopsy of chorionic villi |
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What is the prognosis of Sickle Cell Anemia?
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- Highly variable
- Improved supportive car, increased those living into adulthood - 50% live beyond 50 |
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What drugs/treatments are used to treat patients with Sickle Cell Anemia?
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- Penicillin - prophylactic prevention of pneumococcal infections
- Hydroxyurea - inhibits DNA synthesis - reduces painful crises and lessens anemia - Bone marrow transplantation - potential to be curative |
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What are the effects of Hydroxyurea?
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Reduces painful crises and lessens anemia
- ↑ RBC levels of HbF - Anti-inflammatory effect (inhibits WBCs) - ↑ RBC size → ↓ mean cell hemoglobin concentration (MCHC) - Metabolism to NO - potent vasodilator and inhibitor of platelet aggregation |
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What causes Thalassemias?
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- Decreased synthesis of α- or β-globin chains
- Inherited disorder, autosomal co-dominant |
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What causes the problems in Thalassemias?
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- Deficiency of Hb
- Relative excess of the unaffected globin chain (eg, decreased synthesis of β chains leads to extra α chains) |
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How many genes are there for globin chains? Which chromosomes?
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- Two α-globin genes on chromosome 11
- Single β-globin gene on chromosome 16 |
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What are the degrees of β-Thalassemias?
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- β-Thalassemia Minor (aka "Trait")
- β-Thalassemia Intermedia - β-Thalassemia Major |
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How are the mutations for β-Thalassemia categorized?
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- β° - no β-globin chains are produced
- β⁺ - reduced (but detectable) β-globin synthesis - More than 100 different causative mutations, a majority consisting of single-base changes (gene deletions rarely are the cause) |
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What genes does a patient with β-Thalassemia Minor have? Symptoms?
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- One normal allele
- One abnormal β° or β⁺ allele - AKA β-Thalassemia trait - Asymptomatic or mildy symptomatic |
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What genes does a patient with β-Thalassemia Intermedia have? Symptoms?
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- Two β⁺ alleles
- Milder disease than β-Thalassemia major |
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What genes does a patient with β-Thalassemia Major have? Symptoms?
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- Any two β° and β⁺ alleles
- Most severe form of disease |
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What is the mechanism of the mutations responsible for β-Thalassemias?
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- Mutations leading to aberrant RNA splicing (most common cause)
- May disrupt normal RNA splice junctions (β°) or create a new splice junction (β⁺) - May lower rate of transcription by mutating β-globin promotor (β⁺) - May cause a premature "stop" codon (β°) - More than 100 different causative mutations, a majority consisting of single-base changes (gene deletions rarely are the cause) |
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What mechanisms cause the anemia in β-thalassemia?
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↓ Synthesis of β-globin:
- Inadequate HbA formation → Hypochromic and Microcytic Imbalance of α-globin and β-globin: - Excess unpaired α-globin aggregates into insoluble precipitates → damage membranes of RBCs and precursors → ineffective erythropoiesis - Those that are produced have ↓ lifespan d/t extravascular hemolysis |
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What are the effects of ineffective hematopoiesis in β-thalassemia?
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- Leads to inappropriate increase in absorption of dietary iron (caused by inappropriately low levels of hepcidin)
- Leads to iron overload |
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What is hepcidin? Effect?
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- Negative regulator of iron absorption
- Low levels cause inappropriately increased iron absorption from GI |
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What kind of mutations cause α-thalassemias?
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Deletions involving one or more of the α-globin genes
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What determines the severity of α-thalassemias?
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Proportional to the number of α-globin chains missing
- 1: silent-carrier state (asymptomatic) - 2: α-Thalassemia trait (asymptomatic, "like minor") - 3: relative excess of β-globin or γ-globin (early) (severe, "like intermediate") - 4: lethal in utero (no O2 delivering capacity) ("like major") |
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|
What happens if you have 3 of 4 α-globin genes mutated?
|
- Severe disease
- Similar to β-thalassemia intermedia - Excess of β-globin or γ-globin (early in life) that forms HbH (β4 tetramer) and Hb Bart (γ4 tetramer) - These are less membrane damaging than free α-globin chains found in β-thalassemias - β4 and γ4 tetramers have high affinity for O2 - ineffective for delivering O2 to tissues |
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|
How does α-Thalassemia compare to β-Thalassemia?
|
- HbH (β4) and HbBart (γ4) cause less membrane damage than free α-globin chains (from β-thalassemia)
- But HbH and HbBart have abnormally high affinity for O2 so they are ineffective at delivering O2 to tissues |
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What is the appearance of RBCs in a PB smear from β-thalassemia minor and α-thalassemia trait?
|
- Small (microcytic)
- Pale (hypochromic) - Regular shape - Often target cells w/ ↑ surface area / volume ratio |
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What is the appearance of RBCs in a PB smear from β-thalassemia major?
|
- Microcytosis (small)
- Hypochromia (pale) - Poikilocytosis (variation in cell size) - Anisocytosis (variation in cell shape) - Normoblasts (nucleated RBCs that reflect underlying erythropoietic drive) |
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|
What anatomic changes occur because of β-thalassemia major?
|
Similar to other hemolytic anemias, but profound:
- Skeletal deformities - Splenomegaly, hepatomegaly, and lymphadenopathy - Growth retardation - Cachexia - Hemosiderosis - Erythroid hyperplasia |
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|
What anatomic changes occur because of β-thalassemia intermedia and HbH disease?
|
- Splenomegaly
- Erythroid hyperplasia - Growth retardation (less severe than for β-thalassemia major) |
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|
What changes occur because of β-thalassemia minor and α-thalassemia trait?
|
- Asymptomatic
- If anything a mild microcytic hypochromic anemia - Normal life expectancy |
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|
What kind of treatment is necessary for β-thalassemia? Effects?
|
- Repeated blood transfusions - improves anemia and reduces skeletal deformities
- Iron chelators - to prevent systemic iron overload (fatal) - Bone marrow transplant - treatment of choice |
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|
How do you diagnose β-thalassemia major?
|
- Clinical suspicion
- Hb electrophoresis shows ↓ or absent HbA and ↑ HbF |
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|
How do you diagnose β-thalassemia minor?
|
Hb electrophoresis:
- ↓ HbA1 - ↑ HbA2 |
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|
How do you diagnose HbH?
|
Detection of β4 tetramers in electrophoresis
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|
What is the most common cause of hemolytic anemias caused by oxidative injury?
|
Glucose-6-Phosphate Dehydrogenase Deficiency
- Responsible for synthesizing GSH - Without sufficient GSH, RBCs are vulnerable to oxidative injury and leads to hemolytic anemia |
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|
What is the function of GSH (reduced glutathione)?
|
Inactivates endogenous and exogenous oxidants which can injure RBCs
|
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|
What causes a Glucose-6-Phosphate Dehydrogenase Deficiency? Implications?
|
- G6PD gene is on X chromosome
- Variants in this gene, eg G6PD A-, have normal enzymatic activity but decreased half-life - Older G6PD A- RBCs become progressively deficient in enzyme activity and reduced form of glutathione (GSH) - Renders these cells sensitive to oxidant stress - Leads to hemolytic anemia |
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|
What are the symptoms of Glucose-6-Phosphate Dehydrogenase Deficiency?
|
No symptoms until patient is exposed to an environment factor:
- Infectious agent that produces oxidants - Drugs that produce oxidants |
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|
What drugs produce oxidants and can damage RBCs with Glucose-6-Phosphate Dehydrogenase Deficiency? How long does it take after taking the drugs to get the damage?
|
- Anti-malarials
- Sulfonamides - Nitrofurantoin - Phenacetin - Aspirin (large doses) - Vitamin K derivatives Usually takes 2-3 days to develop hemolysis |
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|
How does infection affect patients with Glucose-6-Phosphate Dehydrogenase Deficiency?
|
- Infections induce phagocytes to generate oxidants as part of the normal host response
- These oxidants (eg, H2O2) normally sopped up by GSH - Because GSH is limited, oxidants are free to attack RBCs (globin chains) |
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|
What happens to RBCs that are attacked by oxidants d/t lack of GSH (d/t Glucose-6-Phosphate Dehydrogenase Deficiency)?
|
- Oxidants attack RBC components like the globin chains
- Oxidized Hb denatures and precipitates forming intracellular inclusions called Heinz bodies - These damage the cell membranes sufficiently to cause intravascular hemolysis - Other less damaged cells lose deformability and suffer when splenic phagocytes try to pluck them out creating "bite cells" - These cells become trapped upon recirculation in spleen and destroyed by phagocytes (extravascular hemolysis) |
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|
What are Heinz bodies?
|
Intracellular inclusions / precipitate of denatured Hb
(caused by Glucose-6-Phosphate Dehydrogenase Deficiency and not enough GSH) |
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|
What causes bite cells?
|
Splenic phagocytes attempt to pluck out the Heinz Bodies
(caused by Glucose-6-Phosphate Dehydrogenase Deficiency) |
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|
How is Glucose-6-Phosphate Dehydrogenase Deficiency inherited? How does this impact who is affected by the disease?
|
- X-linked
- RBCs of affected males are uniformly deficient and vulnerable to oxidative injury - In heterozygous females, random inactivation of one X chromosome creates two populations, one normal and other G6PD-deficient - Most carrier females are unaffected except for those w/ a large proportion of deficient RBCs ("unfavorable lyonization") |
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|
What cells are affected by Glucose-6-Phosphate Dehydrogenase Deficiency?
|
Older RBCs that have run out of GSH
|
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|
What is the course of drug-induced Glucose-6-Phosphate Dehydrogenase Deficiency hemolysis?
|
Since the marrow compensates for the anemia by producing new resistant RBCs, the hemolysis abates even if the drug exposure continues
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|
What Glucose-6-Phosphate Dehydrogenase variant is found in the Middle East? Effects?
|
G6PD Mediterranean - enzyme deficiency and hemolysis that occur on exposure to oxidants is more severe
|
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|
What is the only hemolytic anemia that results from an ACQUIRED somatic mutation in myeloid stem cells?
|
Paroxysmal Nocturnal Hemoglobinuria
|
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|
What is the cause of Paroxysmal Nocturnal Hemoglobinuria?
|
- Acquired somatic mutation in PIGA gene (X-chromosome) in myeloid stem cells
- PIGA is required for synthesis of Phosphatidylinosital Glycan (PIG) - PIG is a membrane anchor that limits activation of complement *PIGA-deficient precursors give rise to RBCs that are inordinately sensitive to complement-mediated lysis |
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|
What is PIG? What is it necessary for?
|
PIG = Phosphatidylinosital glycan = membrane anchor that limits activation of complement
- Required by RBCs - WBCs are also deficient in these protective proteins but nucleated cells are generally less sensitive to complement than RBCs |
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|
What is the reason for the name Paroxysmal Nocturnal Hemoglobinuria?
|
Fixation of complement is enhanced by the slight decrease in blood pH that accompanies SLEEP (owing to CO2 retention)
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|
What are the clinical problems with Paroxysmal Nocturnal Hemoglobinuria?
|
- Chronic low level hemolysis → anemia
- Venous thrombosis |
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|
What is the genetic relationship to Paroxysmal Nocturnal Hemoglobinuria?
|
- PIGA gene is X-linked and somatically acquired
- Because it is X-linked, only a single mutation is sufficient to give rise to PIGA deficiency - Mutations must occur in EARLY MYELOID PROGENITOR w/ self-renewal capacity |
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|
It has been found that normal individuals have small numbers of BM cells w/ PIGA mutations, why aren't they affected?
|
- Clinically evident Paroxysmal Nocturnal Hemoglobinuria occurs only in rare instances in which PIGA mutant clone has a survival advantage
- Eg, Primary BM Failure (aplastic anemia) which is often caused by immune-mediated destruction or suppression of marrow stem cells - PIGA deficient stem cells somehow escape immune attack and replace normal marrow elements |
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|
How can you treat Paroxysmal Nocturnal Hemoglobinuria? Effects?
|
Targeted therapy w/ Ab that inhibits C5b-C9 membrane attack complex
- Effective in diminishing both hemolysis and thrombotic complications - Increased risk for Neisseria infections (including meningococcal sepsis) |
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|
What happens in Immunohemolytic Anemias?
|
- Develop Abs that recognize determinants on RBC membranes
- Leads to hemolytic anemia |
|
|
What causes the presence of Abs against RBC membranes in Immunohemolytic Anemias?
|
- May arise spontaneously
- May be induced by exogenous agents such as drugs or chemicals |
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|
How are Immunohemolytic Anemias classified?
|
- Nature of Ab
- Presence of predisposing conditions |
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|
How do you diagnose Immunohemolytic Anemias?
|
Direct Coombs antiglobulin test
- Detection of Abs and/or complement on RBCs - Patient's RBCs incubated w/ Abs against human Ig or complement - (+) test causes RBCs to clumb / agglutinate Indirect Coombs Test - Assess ability of patient's serum to agglutinate test RBCs bearing defined surface determinants - Used to characterize target of Ab |
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|
What are the types of Immunohemolytic Anemias?
|
- Warm Antibody Immunohemolytic Anemia
- Cold Antibody Immunohemolytic Anemia |
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|
What kind of immunoglobulins cause Warm Antibody Immunohemolytic Anemia?
|
Usually IgG, rarely IgA, antibodies that are active at 37°C
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|
What are the causes Warm Antibody Immunohemolytic Anemia?
|
- >60% idiopathic (primary)
- 25% secondary to underlying dz affecting immune system (eg, SLE) or induced by drugs |
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|
What causes hemolysis in Warm Antibody Immunohemolytic Anemia?
|
- Results from opsonization of RBCs by auto-antibodies → erythrophagocytosis in spleen and elsewhere
- Incomplete consumption (nibbling) of RBCs by macrophages removes membrane → spherocytes → destroyed in spleen |
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|
What is the severity of Warm Antibody Immunohemolytic Anemia normally? How does this affect treatment?
|
- Variable, but usually chronic mild anemia
- Moderate splenomegaly - Requires no treatment |
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|
What kind of drugs can induce Warm Antibody Immunohemolytic Anemia? What happens?
|
- α-Methyldopa induces auto-antibodies against intrinsic RBC constituents, in particular Rh blood group Ags
- Drugs somehow alter the immunogenicity of native epitopes and circumvent T cell tolerance - Penicillin induces an antibody response by binding covalently to RBC proteins → Abs bind to drug and may fix complement or act as opsonins → hemolysis - Quinidine |
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|
What kind of immunoglobulins cause Cold Antibody Immunohemolytic Anemia?
|
Usually low-affinity IgM that bind to RBC membranes only at temp. <30°C
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|
Where do antibodies causing Cold Antibody Immunohemolytic Anemia bind?
|
Bind RBCs that are <30°C which is commonly in distal parts of body (eg, ears, hands, and toes) in cold weather
|
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|
What happens when IgM Abs bind RBCs in Cold Antibody Immunohemolytic Anemia?
|
- IgM Abs must bind < 30°C
- Latter steps of complement fixation cascade occur inefficiently at temp < 37°C - As a result, most cells w/ bound IgM pick up some C3b but are not lysed intravascularly - When these cells travel to warmer areas, weakly bound IgM is released but C3b remains - Because C3b is an opsonin, cells are phagocytosed by macrophages mainly in spleen and liver (extravascular hemolysis) |
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|
How do RBCs affected by Cold Antibody Immunohemolytic Anemia interact with each other?
|
- Pentavalent IgM cross-links RBCs and causes them to clump (agglutinate)
- Sludging of blood in capillaries d/t agglutination often produces Raynaud phenomenon in extremities |
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|
When do cold agglutinins sometimes appear transiently?
|
During recovery from pneumonia caused by Mycoplasma species and infectious mononucleosis, produces a mild anemia
|
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|
More important, chronic forms of Cold Antibody Immunohemolytic Anemia occurs when?
|
In association w/ certain B cell neoplasms (eg, lymphoplasmacytic lymphoma) or as idiopathic conditions
|
|
|
What neoplasms are associated with Warm and Cold Antibody Immunohemolytic Anemia?
|
- Warm: B cell neoplasms (eg, chronic lymphocytic leukemia = CLL)
- Cold: B cell lymphoid neoplasms (eg, lymphoplasmacytic lymphoma = LPL) |
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|
What kind of conditions can cause hemolytic anemias from mechanical trauma to RBCs?
|
- Traumatic Hemolysis: repeated physical blows (eg, marathon racing, karate chopping, bongo drumming, etc) but not clinically significant
- Defective cardiac valve prostheses (blender effect) that creates sufficiently turbulent blood flow to shear RBCs - Microangiopathic hemolytic anemia - small vessels are obstructed or narrowed (eg, Disseminated Intravascular Coagulation = DIC, narrowed d/t fibrin) - Others: Malignant HTN, SLE, hemolytic uremic syndrome, disseminated cancer |
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|
What is the morphological appearance of cells affected by mechanical trauma?
|
Schistocytes = "burr cells", "helmet cells", and "triangle cells"
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|
What kind of hemolysis occurs in Immunohemolytic Anemias?
|
- Opsonization and extravascular hemolysis
- Uncommonly, complement fixation and intravascular hemolysis |
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|
How many people are affected by Malaria? How many die of it per year?
|
- 500 million affected
- Kills 1 million/year |
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|
Where is Malaria endemic?
|
Asia and Africa (but seen all over world d/t travel)
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|
|
What causes Malaria?
|
Bite of female Anopheles mosquitos:
* Plasmodium falciparum → tertian malaria - Plasmodium malariae - Plasmodium vivax - Plasmodium ovale |
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|
Which causes of Malaria cause a high fatality rate?
|
Plasmodium falciparum
|
|
|
Which causes of Malaria are relatively benign?
|
- Plasmodium malariae
- Plasmodium vivax - Plasmodium ovale |
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|
What is the pathogenesis of Plasmodia / Malaria?
|
- Sporozoites introduced from saliva
- Infect liver cells immediately - Parasite rapidly multiplies in liver to form a schizont containing thousands of merozoites - Days to weeks later, infected hepatocytes release merozoites - Merozoites infect RBCs and continue asexual reproduction to make more merozoites or gametocytes - Gametocytes are capable of infecting new mosquitos - Malaria develops into trophozoites w/ distinct appearance (distinguishable on stained thick smear of PB) - Asexual phase complete when trophozoites give rise to new merozoites (which escape by lysis) |
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|
What form of Plasmodia enter the human host through the mosquito saliva? What do they do first?
|
Sporozoite - infect liver cells
|
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|
What do the Plasmodia sporozoites that infect liver cells form?
|
Forms a Schizont via rapid multiplication
|
|
|
What is found within Schizonts?
|
Thousands of merozoites which are released from infected hepatocytes days to weeks later
|
|
|
What infects RBCs in Malaria?
|
Merozoites (released from Schizonts in hepatocytes)
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|
What happens when the Merozoites infect the RBCs?
|
- Continue asexual reproduction to make more merozoites or gametocytes
- Gametocytes are capable of infecting new mosquitos |
|
|
How can you distinguish the different causes of Malaria?
|
Peripheral blood smear appropriately stained
- Species can be differentiated by distinctive appearance of trophozoites |
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|
When is the asexual phase of Plasmodia infection complete?
|
When trophozoites give rise to new merozoites (which escape by lysis)
|
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|
How frequently are new merozoites released from RBCs? Implications?
|
- P. vivax, P. ovale, and P. falciparum every 48 hours
- P. malariae every 72 hours - This causes episodic shaking, chills, and fever that coincide with the release of merozoites |
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|
What are the clinical features of Malaria?
|
- Episodic shaking, chills, and fever (coincides w/ merozoite release)
- Hemolytic anemia - Discoloration of spleen, liver, LNs, and BM d/t brown malarial pigment derived from Hb (hematin) that is released from ruptured RBCs - Hyperplasia of mononuclear phagocytes → massive splenomegaly and occasional hepatomegaly |
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|
How does Malaria affect the brain? Mechanism?
|
Fatal falciparum malaria involves brain = Cerebral Malaria
- Infection of RBCs induces appearance of positively charged surface knobs - Contains parasite-encoded proteins that bind to adhesion molecules on activated endothelium - Binds endothelial CAMs (eg, ICAM-1) → trapping of RBCs in post-capillary venules (which can be in brain) |
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|
What are the symptoms of Cerebral Malaria? Timeline?
|
- Rapidly progressive
- Convulsions, coma, and death - Within days to weeks |
|
|
What is the usual clinical course of Malaria?
|
- Usually chronic course
- May be punctuated by "Blackwater Fever" → massive intravascular hemolysis, hemoglobinemia, hemoglibinuria, and jaundice |
|
|
How do you treat Malaria? Efficacy?
|
- Appropriate chemotherapy, usually good prognosis
- Drug-resistant strains make Plasmodium falciparum difficult to treat - Early diagnosis and treatment are important |
|
|
What are the types of Hemolytic Anemia?
|
- Hereditary Spherocytosis
- Sickle Cell Anemia - Thalassemias (α and β) - Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency - Immunohemolytic Anemias - Malaria |
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|
What are the types of Anemias of Diminished Erythropoiesis?
|
- Iron Deficiency Anemia
- Anemia of Chronic Disease - Megaloblastic Anemia - Aplastic Anemia - Myelophthistic Anemia |
|
|
What type of anemia is caused by bone marrow failure?
|
Aplastic Anemia (type of Anemia of Diminished Erythropoiesis)
|
|
|
What type of anemia is caused by systemic inflammation?
|
Anemia of Chronic Disease (type of Anemia of Diminished Erythropoiesis)
|
|
|
What type of anemia is caused by bone marrow infiltration by tumor or inflammatory cells?
|
Myelophthisic Anemia (type of Anemia of Diminished Erythropoiesis)
|
|
|
What is the most frequent type of anemia in the US?
|
Iron Deficiency Anemia
|
|
|
What is the most frequent type of anemia in the world?
|
Iron Deficiency Anemia
|
|
|
What is the normal total body iron mass for men and women?
|
- Men: 3.5 g
- Women: 2.5 g |
|
|
How is iron dispersed in the body?
|
- 80% in Hemoglobin
- 15% in Hemosiderin and Ferritin-bound iron (iron storage pool) - Remainder in Myoglobin, Iron-containing Enzymes (eg, catalase, cytochromes), and iron storage pool |
|
|
What is are the components of the Iron Storage Pool?
|
- Hemosiderin
- Ferritin-bound iron - Found in liver, spleen, BM, and skeletal muscle |
|
|
What are the methods of estimating the Iron Storage Pool in the liver, spleen, BM, and skeletal muscle?
|
- Serum ferritin - largely derived from storage pool
- Bone Marrow iron - reliable but more invasive |
|
|
How is iron transported within the plasma? How saturated is this protein?
|
Bound to protein Transferrin - 33% saturated
|
|
|
What normal serum iron level in men and women? What is the total iron-binding capacity of serum?
|
- Men: 120 µg/dL
- Women: 100 µg/dL - Total capacity: 300-350 µg/dL (because only 33% of Transferrin is usually saturated) |
|
|
How much iron is lost per day? How? Why this amount?
|
- Limited to 1-2 mg/day through shedding of mucosal and skin epithelial cells
- Limited d/t evolutionary pressure to retain iron |
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|
How is iron balance maintained?
|
Regulating the absorption of dietary iron
|
|
|
How much iron is found in the average Western diet? What are the sources of iron? How much of this is absorbed?
|
- Consume: 10-20 mg of iron / day
- Found in meat/poultry (heme form) and inorganic iron in vegetables (non-heme) - 20% of heme iron and 1-2% of non-heme iron is absorbable |
|
|
Where is iron absorbed in the GI tract?
|
Duodenum
|
|
|
What are the steps of iron absorption from the gut?
|
1. Non-heme iron converted from Fe3+ → Fe2+ by Ferric Reductase
2. Fe2+ is transported across apical membrane by Divalent Metal Transporter-1 (DMT-1) 3. Ferroportin then moves iron from cytoplasm to plasma across basolateral membrane 4. Hephaestin and Ceruloplasmin oxidize Fe2+ → Fe3+ 5. Binds to Transferrin in the plasma |
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|
In what form is non-heme iron in the lumen of the gut?
|
Fe3+
|
|
|
In what form is non-heme iron in the epithelial cells of the gut?
|
Fe2+ (reduced by Ferric Reductase)
|
|
|
In what form is non-heme iron in the plasma (after being absorbed from gut)?
|
Fe3+ (oxidized by Hephaestin and Ceruloplasmin
|
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|
What transporter brings Fe2+ into the cytoplasm of the epithelial cells from the gut?
|
DMT1 (Divalent Metal Transporter-1)
|
|
|
What transporter brings Fe2+ into the plasma from the cytoplasm of the epithelial cells of the gut?
|
Ferroportin 1
|
|
|
What is the function of Ferroportin 1? How is the activity controlled?
|
- Transports Fe2+ into the plasma from the cytoplasm of epithelial cells in the gut (also in other tissues)
- Activity inhibited by Hepcidin (which is elevated when the body is replete w/ iron and erythropoietic activity is normal) |
|
|
If Ferroportin 1 (transporter) is inhibited, what happens to the iron that is stuck in the cytoplasm of the epithelial cells?
|
It is lost by shedding of epithelial cells
|
|
|
What happens to the iron absorption mechanism when the body has sufficient iron and erythropoietic activity is normal?
|
- Plasma Hepcidin levels are HIGH
- Hepcidin binds Ferroportin and induces its internalization - This DOWN-regulates Ferroportin activity and traps most of the absorbed iron in the epithelial cells - Duodenal epithelial cells are eventually shed into the gut |
|
|
What happens to the iron absorption mechanism when the body has insufficient iron and erythropoietic activity is abnormal?
|
- Plasma Hepcidin levels are LOW
- This UP-regulates Ferroportin activity - Iron is transported into the plasma and bound to Transferrin |
|
|
What are the most common causes of Iron Deficiency Anemia in the Western world?
|
Chronic Blood Loss:
- GI tract (eg, peptic ulcers, colonic cancer, hemorrhoids) - Female genital tract (eg, menorrhagia=heavy, metrorrhagia=abnormal, cancer) - Very rarely low dietary intake |
|
|
What are the most common causes of Iron Deficiency Anemia in the developing world?
|
- Low intake
- Poor bioavailability of iron d/t predominantly vegetarian diets |
|
|
In general what are the causes of Iron Deficiency Anemia?
|
- Chronic blood loss (GI or female genital tract)
- Low intake / poor bioavailability of vegetarian diet - Increased demands (pregnancy and infancy) - Malabsorption (celiac disease or after gastrectomy) |
|
|
Regardless of the cause, how does iron deficiency develop?
|
1. First iron stores are depleted
2. Decline in serum Ferritin and absence of stainable iron in bone marrow 3. Decrease in serum Iron 4. Rise in serum Transferrin 5. Ultimately, ability to synthesize Hb, Mb, and other iron-containing proteins is diminished 6. Leads to microcytic anemia |
|
|
What are the degrees of an Iron Deficiency Anemia?
|
- Usually mild and asymptomatic
- Severe: non-specific manifestations, weakness, listlessness, and pallor |
|
|
What are some possible clinical features of Iron Deficiency Anemia?
|
- Impaired work and cognitive performance
- Reduced immunocompetence - Thinning, flattening, and "spooning" of the fingernails - Pica - desire to consume non-food stuff like dirt or clay |
|
|
What is the appearance of Iron Deficiency Anemia on a PB smear?
|
- Microcytic (small)
- Hypochromic (lighter color) |
|
|
What are the diagnostic criteria for Iron Deficiency Anemia?
|
- Anemia
- Hypochromic and microcytic RBC indices - Low serum ferritin and iron levels - Low transferrin saturation - Increased total iron-binding capacity - Response to iron therapy - Also, often platelet count is elevated |
|
|
How does epo respond to Iron Deficiency Anemia? Effect on BM?
|
- Epo is increased
- BM response is blunted d/t iron deficiency - Marrow cellularity is only slightly increased |
|
|
What should you think if your patient is well-nourished but has microcytic, hypochromic anemia?
|
It is not Iron Deficiency Anemia, rather it is a symptom of some underlying disorder
|
|
|
What is the most common form of anemia in hospitalized patients?
|
Anemia of Chronic Disease
|
|
|
What causes Anemia of Chronic Disease?
|
Suppression of erythropoiesis by systemic inflammation
|
|
|
What kind of disorders are associated with Anemia of Chronic Disease?
|
- Chronic microbial infections: osteomyelitis, bacterial endocarditis, and lung abscesses
- Chronic immune disorders: rheumatoid arthritis and regional enteritis - Neoplasms: Hodgkin lymphoma and carcinoma of the lung and breast |
|
|
What chronic microbial infections are associated with Anemia of Chronic Disease?
|
- Osteomyelitis
- Bacterial endocarditis - Lung abscesses |
|
|
What chronic immune disorders are associated with Anemia of Chronic Disease?
|
- Rheumatoid Arthritis
- Regional Enteritis |
|
|
What neoplasms are associated with Anemia of Chronic Disease?
|
- Hodgkin Lymphoma
- Carcinomas of lung and breast |
|
|
What is the pathogenesis responsible for Anemia of Chronic Disease?
|
↑ Hepcidin:
- Synthesis stimulated by IL-6 - Blocks transfer of iron to erythroid precursors by down-regulating ferroportin in macrophages ↓ Erythropoietin: - Chronic inflammation blunts synthesis in kidney - Decreases RBC production in BM |
|
|
What are the diagnostic features / lab findings of Anemia of Chronic Disease?
|
Same as Iron-Deficiency Anemia:
- Serum iron levels usually are usually low - RBCs may be hypochromic and microcytic Distinct from Iron-Deficiency Anemia: * ↑ Storage iron in BM * ↑ Serum ferritin concentration * ↓Total iron-binding capacity |
|
|
How can you treat Anemia of Chronic Disease?
|
Improve anemia / treat symptoms:
- Administration of erythropoietin - Administration of iron Cure: - Treat underlying chronic disease |
|
|
What are the principal causes of Megaloblastic Anemia?
|
- Folate deficiency
- Vitamin B12 deficiency |
|
|
What are folate and vitamin B12 both used for?
|
DNA synthesis
|
|
|
What is the morphological appearance of Megaloblastic Anemia?
|
Cellular Gigantism:
- Megaloblasts: enlarged erythroid precursors → Macrocytes: abnormally large RBCs - Granulocyte precursors are also enlarged |
|
|
Why is there Cellular Gigantism (enlarged cells) in Megaloblastic Anemia?
|
Defect in DNA synthesis that impairs nuclear maturation and cell division
|
|
|
What are the cellular implications of the defects in DNA synthesis in Megaloblastic Anemia?
|
- Synthesis of RNA and cytoplasmic elements is normal and outpaces that of nucleus = Nuclear-Cytoplasmic Asynchrony
- Contributes to anemia in several ways - Pancytopenia (anemia, thrombocytopenia, and granulocytopenia) |
|
|
What does the term Nuclear-Cytoplasmic Asynchrony mean?
|
Synthesis of RNA and cytoplasmic elements is normal and outpaces that of nucleus in Megaloblastic Anemia
|
|
|
How does Nuclear-Cytoplasmic Asynchrony contribute to Megaloblastic Anemia?
|
- Many megaloblasts are so defective in DNA synthesis that they undergo apoptosis in BM = Ineffective Hematopoiesis
- Others mature into RBCs after fewer cell divisions, further diminishing the output of RBCs - Granulocyte and platelet precursors are also affected (pancytopenia) |
|
|
What are the morphological features in the bone marrow of Megaloblastic Anemia?
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- BM: hypercellular w/ megaloblasts
- Megaloblasts: larger erythroid progenitors w/ delicate finely reticulated nuclear chromatin and abundant basophilic chromatin - Giant Metamyelocytes: granulocytic precursors have nuclear-cytopasmic asynchrony - Megakaryocytes: larger w/ multi-lobed nuclei |
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What are the morphological features in the peripheral blood of Megaloblastic Anemia?
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- Hypersegmented Neutrophils: >5 lobes
- Egg-shaped macro-ovalocytes: RBCs w/ MCV >110fL (normal 82-92fL) - Large misshapen platelets |
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What can cause a Folate (Folic Acid) Deficiency Anemia (type of Megaloblastic Anemia)?
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- Poor diet (poor, indigent, elderly)
- Increased metabolic needs (pregnancy, patients w/ chronic hemolytic anemia) - Drugs: Phenytoin (inhibit absorption) and Methotrexate (inhibit metabolism) - Celiac Disease and Tropical Sprue (impair uptake) |
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How do you obtain Folate in the food? Challenges?
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- Folate is present in nearly all foods but is destroyed by 10-15 minutes of cooking
- Best sources are fresh uncooked vegetables and fruits - Found in polyglutamate form and must be absorbed in monoglutamate form, this conversion is hampered by acidic food and substances in beans/legumes |
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What drugs affect Folate? How?
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- Phenytoin - inhibits folate absorption
- Methotrexate - inhibits folate metabolism |
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Where is Folate absorbed? Implications?
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- Upper third of the small intestine
- Malabsorptive disorders that affect this level of the gut, such as Celiac disease and Tropical Sprue, can impair folate uptake |
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What are the forms of Folate? Conversion?
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- After absorption it is transported as "monoglutamate" form
- Further metabolized in cells to Dihydrofolate and then to Tetrahydrofolate (THF) by Dihydrofolate Reductase |
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What is the function of Tetrahydrofolate (THF)? Implications of a deficiency?
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- Acts as an acceptor and donor of 1C units
- Required for synthesis of purines and thymidylate (building blocks of DNA) - Deficiency accounts for defect in DNA replication underlying Megaloblastic Anemia |
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What are the symptoms of Folate (Folic Acid) Deficiency Anemia (type of Megaloblastic Anemia)?
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- Onset is insidious and non-specific
- Weakness and fatigability - Symptoms may refer to alimentary tract, such as sore tongue (NO neurologic abnormalities) |
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Morphologically how does Vitamin B12 (Cobalmin) Deficiency Anemia compare to Folate (Folic Acid) Deficiency Anemia?
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- Both cause identical Megaloblastic Anemia
- Vit B12 deficiency can also cause a demyelinating disorder of the peripheral nerves and spinal cord |
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What can cause Vitamin B12 (Cobalmin) Deficiency Anemia (type of Megaloblastic Anemia)?
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- Defects involving Intrinsic Factor (aka Pernicious Anemia) - most common
- Long-standing malabsorption, confined mainly to strict vegans - After gastrectomy or ileal resection - disorders that disrupt function of distal ileum (eg, Crohn disease, Tropical Sprue, and Whipple disease) - Older persons w/ gastric atrophy and achlorhydia may interfere w/ production of acid and pepsin (necessary for release of B12 from food) |
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What does the term Pernicious Anemia refer to?
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- Vitamin B12 deficiency caused by defects involving intrinsic factor
- Auto-immune reaction against parietal cells and intrinsic factor itself, which leads to gastric mucosal atrophy |
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How is Vitamin B12 (Cobalamin) absorbed?
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1. Peptic digestion releases dietary Vitamin B12
2. Binds to salivary protein Haptocorrin 3. Haptocorrin-B12 complex processed by pancreatic proteases in duodenum 4. B12 is released to attach to Intrinsic Factor 5. IF-B12 complex attaches to Cubulin (receptor for IF) in distal ileum and is taken up into enterocytes 6. Absorbed B12 is transferred across basolateral membrane to plasma Transcobalamin 7. Transcobalamin-B12 complex is delivered to liver and other cells of body |
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What protein does Vitamin B12 bind in the saliva? How and where is it released from this protein?
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- Binds to Haptocorrin
- Processes by pancreatic proteases in duodenum |
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What protein does Vitamin B12 bind in the duodenum? Where does this complex go?
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- Binds to Intrinsic Factor
- Complex passes to distal ileum |
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Where does Intrinsic Factor come from?
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Secreted from parietal cells of gastric fundic mucosa
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What protein does Vitamin B12 bind in the distal ileum? Where does this complex go?
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- Complex of Intrinsic Factor and Vitamin B12 binds to Cubulin (a receptor for IF)
- Taken up into enterocytes - Transferred across basolateral membrane into plasma |
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What protein does Vitamin B12 bind in the plasma? Where does this complex go?
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- Transferred to Transcobalamin as it leaves the enterocyte into the plasma
- Transcobalamin delivers B12 to liver and other cells of the body |
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Where can you obtain Vitamin B12 in your diet? Challenges?
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- All food derived from animals, including eggs and dairy products
- Resistant to cooking and boiling (unlike Folic Acid) - Even bacterial contamination of water and non-animal foods can provide adequate amounts |
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What happens to Vitamin B12 once it is absorbed (in terms of elimination)?
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- Handled very efficiently
- Stored in liver - Normally contains reserves to support bodily needs for 5-20 years |
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What associations favor an auto-immune basis for Pernicious Anemia?
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- Auto-Abs present in serum and gastric juice of most patients
- Frequently occurs concomitantly w/ other auto-immune diseases such as Hashimoto thyroiditis, Addison disease, and type I DM - Serum Abs to IF are often present in patients w/ other auto-immune disease |
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What kind of antibodies are found in Pernicious Anemia?
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- Parietal Canalicular Abs - bind to mucosal parietal cells
- Blocking Abs - disrupt the binding of Vit B12 to IF - Intrinsic Factor-B12 Complex Abs - prevent complex from binding to cubulin |
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How does a Vitamin B12 deficiency lead to Megaloblastic anemia?
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- Vitamin B12 is required for the recycling of Tetrahydrofolate (THF)
- THF is the form required for DNA synthesis |
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How can you treat Vitamin B12 (Cobalmin) Deficiency Anemia (type of Megaloblastic Anemia)? Side Effects?
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- Reversed with administration of Folate
- This may worsen the neurologic symptoms - Parenteral Vitamin B12 |
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What neurological symptoms are seen in Megaloblastic anemia? Which type?
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- Seen in Vitamin B12 deficiency
- Associated with demyelination of posterior and lateral columns of the spinal cord - Sometimes begins in peripheral nerves - Severity of neuro sx are not related to degree of anemia |
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What are the clinical features of Vitamin B12 (Cobalmin) Deficiency Anemia (type of Megaloblastic Anemia)?
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- Non-specific: pallor, easy fatigability, in severe cases, dyspnea or CHF
- Mild jaundice possible (d/t destruction of erythroid progenitors) - GI signs/sx (similar to folate deficiency) * Neurological / spinal cord disease - symmetric numbness, tingling, and burning in feet and hands, w/ unsteadiness of gait and loss of position sense esp. in toes |
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What are the neurological symptoms of Vitamin B12 (Cobalmin) Deficiency Anemia (type of Megaloblastic Anemia)?
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- Starts w/ symmetric numbness, tingling, and burning in feet or hands
- Progresses to unsteadiness of gait and loss of position sense especially in toes - Not improved with folate administration or parenteral Vitamin B12 |
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What are patients with Pernicious Anemia at increased risk for?
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Gastric carcinoma
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What are the diagnostic features of Vitamin B12 (Cobalmin) Deficiency Anemia (type of Megaloblastic Anemia)?
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- Low serum B12
- Normal or elevated serum folate - Serum Abs to Intrinsic Factor - Moderate to severe Megaloblastic Anemia - Leukopenia w/ hypersegmented granulocytes - Dramatic reticulocytic response (w/in 2-3 days) to parenteral administration of vitamin B12 |
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What response should you see within 2-3 days of parenteral administration of Vitamin B12 in Vitamin B12 (Cobalmin) Deficiency Anemia (type of Megaloblastic Anemia)?
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Dramatic reticulocytic response
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What are the prominent features of Aplastic Anemia?
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- Multipotent myeloid stem cells are suppressed
- Leads to bone marrow failure and pancytopenia |
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What causes Aplastic Anemia?
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- >50% of cases are idiopathic
- Remainder, an exposure to a known myelotoxic agent can be identified - Sometimes after certain viral infections (most often community-acquired viral hepatitis - but not A, B, or C) |
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What kind of myelotoxic agents have been identified for causing Aplastic Anemia?
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Drugs causing predictable, dose-related, and reversible responses:
- Anti-neoplastic drugs (alkylating agents, anti-metabolites) - Benzene - Chloramphenicol Drugs causing "idiosyncratic" or hypersensitivity reactions: - Small doses of myelotoxic drugs (chloramphenicol) - Sulfonamides (not myelotoxic in others) |
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What is the relationship between hepatitis and Aplastic Anemia?
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- Sometimes AA can arise after certain viral infections
- Community-acquired viral hepatitis is the most common - Specific virus responsible is not known, but hepatitis viruses A, B, and C are not the culprits - Marrow aplasia develops insidiously for several months after recovery from hepatitis and follows a relentless course |
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What are the pathogenic events that may lead to bone marrow failure in Aplastic Anemia?
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Auto-reactive T cells are involved, mechanism not well understood
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How effective is immunosuppressive therapy aimed at T cells for Aplastic Anemia?
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Responds in 70-80% of cases
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What defect is associated with acquired forms of Aplastic Anemia?
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- 5-10% have inherited defects in Telomerase
- Needed for maintenance and stability of chromosomes - Defect in telomerase leads to premature senescence of HSCs - BM cells in up to 50% of sporadic cases have unusually shortened telomeres, possibly by an undiscovered defect in telomerase or of excessive replication of HSCs |
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What other type of anemia is associated w/ marrow aplasia? What is wrong in this disorder?
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Fanconi Anemia - inherited disorder of DNA repair
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What is the morphology of the bone marrow in Aplastic Anemia?
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- Marked hypocellularity
- >90% of intratrabecular space occupied by fat - Limited cellularity consists of lymphocytes and plasma cells |
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What systemic changes occur in Aplastic Anemia?
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- Fatty change in liver
- Hemorrhages d/t thrombocytopenia - Bacterial infections d/t granulocytopenia - Hemosiderosis (iron overload) d/t requirement of transfusions |
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What are the clinical symptoms of Aplastic Anemia?
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- Slowly progressive anemia
- Insidious: weakness, pallor, dyspnea - Thrombocytopenia → petechiae and ecchymoses - Granulocytopenia → minor infections (frequent and persistent) or onset of chills, fever, and prostration (weakness) - NO SPLENOMEGALY |
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What are the morphological properties of Aplastic Anemia on a PB smear?
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- RBCs are normochromic and normocytic (or slightly macrocytic)
- Reticulocytes are reduced (reticulocytopenia) |
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What is the prognosis of Aplastic Anemia?
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- Unpredictable
- Withdrawal of drugs may lead to remission (but exception more than the rule) - Idiopathic form has poor prognosis if untreated |
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How do you treat Aplastic Anemia? Effect?
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- BM Transplant is curative usually in non-transfused patient <40yo (best if you limit the transfusions because they sensitize patients to allo-antigens, producing a high rate of engraftment failure)
- Successful transplant requires "conditioning" w/ high doses of immunosuppressive radiation or chemotherapy - Poor transplantation candidates often benefit from immunosuppressive therapy |
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What causes Myelophthisic Anemia?
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- Extensive infiltration of BM by tumors or other lesions
- Most commonly associated w/ metastatic breast, lung, or prostate cancer - Other tumors, advanced TB, lipid storage disorders, and osteosclerosis can produce similar clinical picture |
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What are the principal manifestations of Myelophthisic Anemia?
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- Anemia
- RBCs are misshapen, some resembling teardrops, in PB - Immature granulocytic and erythrocytic precursors may be present (leukoerythroblastosis) - Thrombocytopenia - WBCs less affected (if anything a mild leukocytosis) |
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How do you treat Myelophthisic Anemia?
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Treat the underlying condition
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