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What are thalassemias?

group of genetic disorders characterized by the lack or decreased synthesis of either alpha or beta globin chains of hemoglobin a
a thalassemia-alpha globin chain synthesis is reduced
b thalassemia-b globin chain synthesis is absent (b0) or deficient (b+)


Alpha thalassemia?

two genes on chromosome 16
4 degrees
alpha thalassemia trait:
--/aa(asian) , -a/-a (black)
HbH disease:
Hydrops fetalis:



one gene on chromosome 11


How does B-thalassemia lead to anemia? hemolytic anemia?

reduced synthesis of B-globin leading to inadequate HgbA formation

relatively excess alpha globulins
-form insoluble aggregates which damage cell membranes-reduce cell membrane plasticity and allow RBCs to be susceptible to phagocytosis


Thalassemia major vs minor?

major: severe disease, reliance on transfusions
minor: asymptomatic, mild or absent anemia, some RBC abnormalities


What is B thalassemias major?

-marrow space is expanded causing skeletal deformities

-hepatosplenomegaly from extramedullary hematopoiesis causes abdominal distention

-multiple transfusions necessary, leading to excessive deposition of iron (death may result from cardiac failure)


What is B-thalassemia minor?

-minor microcytic hypochromic anemia (must be distinguished from an iron deficiency)
-hemoglobin electrophoresis and iron studies are used to make diagnosis
-HgbA2 (a2g2)-increased

Mediterranean patients


What do you see on a blood smear of a patient with B-thalassemia?

target cells
-decrease in hemoglobin in cytoplasm(basketball)-bleb in the membrane in the center


What is paroxysmal nocturnal hemoglobinuria?

the only acquired defect in the red cell membrane

1. stem cell disorder that results from a mutation in the phosphatidylinositol glycan A gene (PIGA)
2. deficiency of GPI anchor
3. lack of expression of GPI linked proteins
such as
-CD55 (DAF)
-C8 binding protein
-->involved in inactivating the complement pathway


What are classical findings in PNH?

1. patient has classic intravascular hemolysis
2. paroxysmal and nocturnal in only 25% of cases
3. infections and venous thrombosis
4. occasional evolution to aplastic anemia or acute leukemia


Some intrinsic abnormalities of RBC caused hemolysis, such as hereditary spherocytosis, G6PD deficiency, sick cell anemia, thalassemia, and PNH, what are some extrinsic abnormalities that can lead to hemolysis of the RBC?

1. antibody mediated
2. mechanical trauma
3. infections
4. chemical injury


What are some examples of mechanical trauma that cause hemolysis?

1. prosthetic cardiac valves
2. narrowing of small vessels and fibrin deposition (microangiopathic hemolytic anemia)
-->presence of schistocytes in peripheral blood


What causes iron deficiency anemia?

1. malabsorption of iron
-low dietary intake not often the cause of deficiency in the us
2. may not meet demand during pregnancy or infancy
3. most common cause of iron deficiency is western world is blood loss!


What is the order of depletion in iron deficiency anemia?

1. stored iron first depleted
-serum ferritin declines, bone marrow iron depleted
2. circulation iron then decreases
-measured serum iron low
3. increased total iron binding capacity (TIBC)
4. hemoglobin eventually decreases
5. RBCs become small with reduced hemoglobin concentration


What are signs of iron deficiency anemia?

1. nails may develop ridges and become spoon shaped
2. tongue may become smooth
3. intestinal malabsorption may develop
4. esophageal webs may appear (rare today)


What does iron deficiency anemia look like on a blood smear?

central pallor is almost entire cell


What leads to megaloblastic anemias?

Disturbances of proliferation and maturation of erythroblasts due to defective DNA synthesis

Two Principle types
1. B12 deficiency
2. folate deficiency



enlarged red cell precursors



enlarged red blood cells


What is the ratio of cytoplasm to nuclei like in megaloblastic anemias?

nuclei are immature and cytoplasm is fully mature: nuclear cytoplasmic asynchrony


What leads to vitamin b12 megaloblastic anemia?

1. inadequate diet-takes a long time
2. increased requirements
3. impaired absorption


What leads vitamin B12 impaired absorption?

1.IF deficiency
2. pancreatitis
3. gastrectomy
4. ileal resection, regional enteritis
5. parasites (fish tapeworm)


What is pernicious anemia?

B12 deficiency secondary to atrophic gastritis with failure of production of intrinsic factor


How does B12 affect THF and DNA synthesis?

transfer of methyl group to B12 so THF can do its DNA job without B12 impaired DNA synthesis


How does B12 affect homocysteine and methionine?

B12 transfers methyl group to homocysteine to make methionine without B12 homocysteine builds up


How does B12 affect succinyl Coenzyme A?

For methylmalonyl coA to make succinyl coA there needs to be B12
-without it there is an increase in methylmalonate and that is associated with CNS symptoms


What are clinical findings of a b12 deficiency?

1. alimentary tract: atrophic glossitis, chronic gastritis

2. blood and bone marrow: megaloblastic anemia, leukopenia with hypersegmented granulocytes, mild to moderate thrombocytopenia

3. CNS findings: involvement of posterolateral spinal tracts, leading to sensory and motor abnormalities
-subacute combined degeneration-->spastic paraparesis, sensory ataxia, lower limb paresthesias


How does someone get a folate deficiency?

-inadequate intake or impaired absorption
-reserves are modest-still does not appear for months unless demand increased


Is there CNS abnormalities in folate deficiency? Can you reverse the problems seen in folate deficiency, what about B12 deficiency?



Can you reverse the problems seen in folate deficiency, what about B12 deficiency?

yes but there is no reversal of CNS abnormalities with B12 deficiency

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