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BIOC Heme-Onc II > Hemoglobinpathies > Flashcards

Hemoglobinpathies Flashcards

1
Q

what are the thalassemias?

A

pathologies characterized by deficiencies in globin chain production (& sometimes a compensatory inc in the other chain)

  • alpha thalassemia
  • beta thalassemia
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2
Q

alpha-thalassemia

  • pathogenesis?
  • variations?
A

caused by a deletion of one or all of the four alpha chain genes

  • four deletion patterns
    • loss of 1 gene - no problem
    • loss of 2 genes - minor changes (anemia)
    • loss of 3 genes = HbH disease
      • formation of B4 tetramers
      • severe anemia
    • loss of 4 genes = HbBarts
      • fatal in utero
        • formation of y chain tetramers
        • hydrops fetalis
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3
Q

in what regions is alpha thalassemia prevalent? why is this is the case?

A

malaria belt - Southeast Asia, Middle East > Africa, Mediterranean

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4
Q

HbH presentation

A

= alpha thalassemia d/t 3 gene deletions

  • presence of B-chain tetramer (black arrows)
    • cause precipitation in erythrocytes → hemolytic anemia
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5
Q

HbBarts presentation

A

alpha thalassemia d/t 4 gene deletions

  • y chain tetramer
    • holds oxygen extremely tightly, cannot deliver it to fetus →
      • hydrops fetalis
      • death
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6
Q

beta thalassemia

  • pathogenesis
  • variations
A
  • can be d/t to variety of mutations =- missense, slice, site, promotor, ect
  • variations = based on decreasing amount of B-globin
    • minor
    • intermedia
    • major
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7
Q

in what regions is beta thalassemia prevalent?

A

malaria belt - Southeast Asia, Middle East > Africa, Mediterranean

(same as alpha-thalassemia)

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8
Q

beta thalassemia - presentation

A
  • alpha-chain tetramers form → dyserythropoiesis →
    • overworked spleen
      • splenomegaly
    • skeletal abnormalities
      • long bones
      • altered skull / maxilla
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9
Q

identify the cause & explain

A

splenomegaly d/t beta-thalassemia

  • alpha globins are less soluble than beta globins. alpha 4 tetramers aggregate in RBCs → damaged RBCs overwork the spleen → spleen hypertrophies → splenomegaly
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10
Q

identify the cause & explain

A

skeletal abnormalities d/t beta thalassemia

  • alpha globins are less soluble than beta globins. alpha 4 tetramers aggregate in maturating RBCs in bone marrow → bone marrow damage
    • long bones
    • abnormally shaped skull maxilla (flat skull)
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11
Q

in what hemoglobinopathies might blood smears show teardrop RBCs?

A
  • thalassemias
  • fibrosis disorders
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12
Q

what are the point mutation hemoglobinopathies?

A

hemoglobinopathies arising from single point mutations in globin gene

  • HbS (sickle cell anemia)
  • HbC
  • HbD, HbE, ect.
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13
Q

sickle cell anemia - pathogenesis

A
  • point mutation hemoglobinopathy
    • Glu → Val at position 6
    • Val, a hydrophobic aa, interacts with hydrophobic patches on adjacent Hb →
      • RBC aggregation, membrane disruption, abnormal cell shape / size
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14
Q

how does sickle cell anemia alter RBC membrane transport?

A
  • inc K+Cl- cotransport out of cell & INC intracellular [Ca+]. leads to
    • intracellular H20 decrease & relative HbS increase → abnormal RBC size/shaoe
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15
Q

how does sickle cell anemia affect membrane composition?

A
  • several structural changes:
    • presence of CAMs (cell-adhesion molecules)
    • change in orientation PL / membrane protein orientation
    • cytoskeletal deformation
  • all of which lead to
    • inc interaction of RBC with vascular endothelium
    • prothrombotic RBCs
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16
Q

the altered composition of RBC membranes in sickle cell anemia leads to what major consequences?

A
  • produces RBCs that
    • interact with vascular endothelium more
    • are pro-thrombotic
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17
Q

in what regions is sickle cell anemia most prevalent? why?

A

in those with endemic _falciparum_ malaria: sickle cell heterozygotes survive malaria, pass on genes

18
Q

describe a blood smear from someone with sickle cell anemia

A
  • RBCs can can be
    • normocytic / normochromic, or
    • show
      • poikilocytosis (abnormal shape)
      • anisocytosis (size variation)
19
Q

summarize the clinical presentation of sickle cell anemia

A

presentation is d/t hemolysis (hyper-bilirubinemia) & RBC aggregation (splenic sequestration):

  • splenic sequestration → splenic infarctions / auto-splenectomy / pain crisis
  • hyperbilirubinemia → jaundice / bilirubin gallstones
  • in children → edema of hands and feet
20
Q

what is splenic sequestration?

in what kind of anemia does if manifest?

A

phenomenon seen in sickle cell anemia.

characterized by presence of a large # of damaged RBCs in splenic capillaries, which can lead to

  • splenic infarction
  • low hematocrit (low# of circulating blood cells)
21
Q

tx of splenic sequestration

A

transfusion.

though it will alleviate the sx of anemia, one must done carefully, such that hematocrit is not to high once sequestration ends

22
Q

dx of sickle cell anemia?

A

two methods

  • southern blot: shows disruption of MST-II cleavage site
  • ASO: shows T→ A missense mutation - modern, commonly used method
23
Q

how is a southern blot used to dx sickle cell anemia?

A
  • it reveals disrupted Mst-II site
    • in HbS, the Glu → Val mutation disrupts cleavage site Mst-II. this missed cleavage results in a longer mutant chain (1.3 kb) as opposed to the 1.1 kb B-chain seen in Hb.
      • two 1.1 kb fragments = normal
      • one 1.1 kb fragment + one 1.3 kb fragment = heterozygous (carrier)
      • two 1.3 kb fragments = HbS
24
Q
A
25
Q

how is allele-specific oligonucleotide analysis (ASO) used to dx sickle cell anemia?

A
  • two probes - one complementary to a normal B-globin nucleotide sequence and the other to the HbS B-globin nucleotide sequence (A where a T should be) are generated
    • hybridization with mutated sequence = HbS
26
Q

Hemoglobin C - pathogenesis

A
  • a point mutation hemoglobinopathy
    • change in Glu → Lys as position 6 of B-globin gene
27
Q

in what regions in HbC disease most prevalent?

A

west africa

28
Q

summarize the clinical presentation of hemoglobin C presentation

A

like sickle cell, HbC causes RBC hemolysis (& thus hyperbilirubinemia) & damage (& thus splenic injury)

  • splenomegaly
  • cholelithiasis (gall-stone formation)
  • crystallization
29
Q

how does HbC disease alter membrane transport in RBCs?

A
  • like in sickle cell, RBC membrane
    • lose K+/Cl- & water → deform/shrink
30
Q

describe a blood smear of someone with HbC disease

A
  • possible presence of
    • spherocytes
    • target cells
    • HbC crystals
31
Q

how does tx with a splenectomy affect the RBC morphology in someone with HbC?

A

it increases the presence of HbC crystals seen in the blood smear

32
Q

compare / contrast the presentation of HbS and HbC

A
  • both can cause:
    • splenomegaly
    • cholelithiasis (gall-stones)
  • only HbS: likely to cause pain crisis
  • only HbC: results in crystals formation
33
Q

Hemoglobin D - pathogenesis

A
  • a point mutation hemoglobinopathy
    • change in Glu → Gln as position 21 of B-globin gene
34
Q

in what regions is HbD prevalent?

A

India, Meditarranean, Africa

35
Q

summarize the clinical presentation of HbD

A

generally asymptomatic, +/- slight anemia

36
Q

HbD can cause a severe sickling disorder when inherited with what other hemoglobinopathy?

A

sickle cell (HbS)

37
Q

Hemoglobin E - pathogenesis

A
  • a point mutation hemoglobinopathy
    • change in Glu → Lys as position 26 of B-globin gene
38
Q

hemoglobin E is prevalent in what regions?

A

“HbE triangle”: southeast Asia, border of Thailand, Loas, Cambodia

39
Q

describe a blood smear in somebody with HbE disease

A
  • may show
    • target cells
    • decreased hemoglobin - larger area of central pallor d/t activation of cryptic splice site
40
Q

summarize the clinical presentation of HbE

A

largely asymptomatic, +/- mild anemia

41
Q

list the mutation in each point mutation hemoglobinpathy

A
  • HbS: position 6: Glu → Val
  • HbC: position 6: Glu → Lys
  • HbD: position 121: Glu → Gln
  • HbE: position 26: Glu → Lys
42
Q

identify each smear

A
  • A: HbSS
  • C: HbSC
  • D: HbCC - target cells + spherocytes + HbC crystals
  • E/F: HbCC post splenectomy - increased # of HbC crystals
  • G: HbDD
  • H/I: HbE/HbEE - target cells + decreased Hb

BIOC Heme-Onc II (3 decks)

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