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Heme / Onc > SM_247b: Congenital Hemolytic Anemias > Flashcards

SM_247b: Congenital Hemolytic Anemias Flashcards

1
Q

Hemoglobin has ___ subunits including ___ and ___

A

Hemoglobin has 4 subunits including 2 alpha globin chains and 2 beta globin chains

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2
Q

In reduced state, heme is covalently bound to ___ and ___

A

In reduced state, heme is covalently bound to O2 and CO

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3
Q

____ and ____ direct production of hemoglobin during development

A

Beta locus on chromosome 11 and alpha locus on chromosome 16 direct production of hemoglobin during development

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4
Q

Describe hemoglobin switching

A

Hemoglobin switching

  • Switch from epsilon to gamma completed by 10 weeks gestational age
  • Embryonic Hb (Zeta2-epsilon2) is replaced by fetal Hb (alpha2-gamma2) which predominates at birth
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5
Q

Describe distribution of functional hemoglobin by 6 months of age

A

Distribution of functional hemoglobin by 6 months of age

  • 90-97% HbA (alpha2-beta2): normal adult Hb
  • 1% HbF (alpha2-gamma2): fetal Hb
  • 2% HbA2 (alpha2-delta2): variant adult Hb
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6
Q

Mutations in Hb affect ____, ____, or ____

A

Mutations in Hb affect solubility, oxygen affinity, or synthesis

  • Beta mutations more common than alpha mutations
  • Genetic basis characterized by point mutations, nucleotide insertions / deletions, crossovers
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7
Q

Describe clinically important structural Hb mutants

A

Clinically important structural Hb mutants

  • Sickle cell phenotypes
  • Thalassemia phenotypes
  • Unstable hemoglobins
  • Abnormal oxygen affinity
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8
Q

Sickle cell mutation is an example of a ____

A

Sickle cell mutation is an example of a balanced polymorphism

  • Heterozygous state confers protection from malarial infection
  • Homozygous state confers risk of premature death
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9
Q

Sickle cell disease is caused by a ___

A

Sickle cell disease is caused by a substitution in the 6th codon of the beta gene

  • Glutamic acid replaced by valine
  • Mutant beta globin chain
  • Sickle hemoglobin
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10
Q

Describe common genotypes of sickle cell disease

A

Common genotypes of sickle cell disease

  • Homozygous / compound heterozygous: Hb SS, Hb SC, Hb S / beta0 or beta+ thalassemia
  • Heterozygous state: Hb C or beta thalassemia trait is clinically insignificant, Hb S trait is associated with medical complications in adult
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11
Q

____ is the primary event in the pathogenesis of sickle cell disease

A

Intracellular polymerization of HbS during deoxygenation is the primary event in the pathogenesis of sickle cell disease

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12
Q

Describe sickle Hb polymerization

A

Sickle Hb polymerization depends on

  • HbS concentration: direct correlation exists between gelation and HbS concentration
  • Oxygenation status: polymerization occurs only in deoxygenated state
  • pH concentration: solubility of deoxygenated HbS is lowest between 6.0 and 7.2
  • HbF and other non-sickle Hb concentration: HbF, HbA, HbA2 have inhibitory effect on sickle polymerization
  • Cation homeostasis / hydration: activated KCl co-transport increases intracellular Hb concentration and polymer formation
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13
Q

____ and ____ are involved in sickle cell dehydration

A

Gardos channel and KCl co-transporter are involved in sickle cell dehydration

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14
Q

In vivo sickling leads to ____ and ____

A

In vivo sickling leads to hemolysis and vaso-occlusion

  • Hemolysis: leads to shortened RBC life span, anemia, and vasomotor dysregulation
  • Vaso-occlusion: leads to pain, disability, and end organ damage
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15
Q

Describe vaso-occlusion in sickle cell disease

A

Vaso-occlusion in sickle cell disease

  • Inflammation, genetic modifiers, hypercoagulability, cell adhesion, oxidative stress, RBC sickling, endothelial dysfunction, inflammation
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16
Q

Adherent ___ interact with sickled RBCs

A

Adherent leukocytes interact with sickled RBCs

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17
Q

Describe diagnosis of sickle cell disease in newborn period

A

Diagnosis of sickle cell disease in newborn period

  • On newborn screening
  • Lack of symptoms at birth explained by protective effect of fetal Hb
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18
Q

Describe the diagnosis of sickle cell disease in an older child

A

Diagnosis of sickle cell disease in an older child

  • Typical peripheral blood smear
  • Predominance of sickle Hb on electrophoresis
  • Laboratory findings: variable anemia, reticulocytosis, and hyperbilirubinemia
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19
Q

Describe clinical spectrum of sickle cell disease

A

Clinical spectrum of sickle cell disease

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20
Q

___ episodes represent the hallmark of sickle cell disease

A

Vaso-occlusive (pain) pisodes represent the hallmark of sickle cell disease

  • Hand-foot syndrome / dactylitis early in childhood
  • Triggers of pain episodes may vary
  • Episodes commonly involve lower back, chest, knees, and long bones
  • Pain may be difficult to differentiate from bone or joint infection
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21
Q

___ is the most common cause of death in children with sickle cell disease

A

Infection is the most common cause of death in children with sickle cell disease

  • High risk with encapsulated organisms: S. pneumoniae, H. influenzae, S. aureus, Salmonella spp.
  • Functional asplenia
  • May trigger complications such as aplastic crisis
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22
Q

Children with sickle cell disease are at greatest risk for infection due to ___

A

Children with sickle cell disease are at greatest risk for infection due to encapsulated organisms

  • S. pneumoniae, H. influenzae, S. aureus, Salmonella spp.
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23
Q

Acute chest syndrome is ___

A

Acute chest syndrome is fever + abnormal CXR + any respiratory symptom

  • Etiology is multifactorial: infection, pulmonary infarction, fat emboli
  • Pain episode is the most common preceding event
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24
Q

Overt ___ may occur in patients with sickle cell disease

A

Overt stroke may occur in patients with sickle cell disease

  • Affected area is usually in the distribution of large vessels
  • Aplastic crisis, acute chest, low O2 are risk factors
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25
Q

Mainstays of treatment for sickle cell disease are ____ and ____

A

Mainstays of treatment for sickle cell disease are preventive measures and therapeutic intervention

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26
Q

Crizalizumab is a ___ used to treat sickle cell disease

A

Crizalizumab is a selectin inhibitor used to treat sickle cell disease

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27
Q

Voxelator is a ___ used to treat sickle cell disease

A

Voxelator is a hemoglobin allosteric modulator used to treat sickle cell disease

28
Q

L-gutamine is an ___ used to treat sickle cell disease

A

L-gutamine is an antioxidant used to treat sickle cell disease

29
Q

RBC membrane is composed of ____ and ____

A

RBC membrane is composed of a fluid lipid bilayer and a network of skeletal and transmembrane proteins

  • Membrane functions to maintain RBC structural integrity, provide strength and flexibility, import iron / electrolytes / water, removes metabolic waste
30
Q

Describe lipid bilayer of RBCS

A

Lipid bilayer of RBCs

  • Comprises 50% of RBC membrane
  • Composed of free cholesterol and phospholipids
  • Organized into planar bilayer
  • Inherent symmetry present = flip-flop
  • Disorganization explained by bilayer coupling theory
31
Q

RBCs with expanded outer layer are ____

A

RBCs with expanded outer layer are echinocytes

32
Q

RBCs with expanded inner layer are ____

A

RBCs with expanded inner layer are stomatocytes

33
Q

Describe membrane proteins of RBCs

A

RBC membrane proteins

  • Classified by: electrophoretic mobility (SDS-polyacrylamide), function (membrane skeleton), location (integral vs peripheral)
  • Integral (traverse lipid bilayer): band 3
  • Peirpheral (interact at membrane surface only): spectrin, ankyrin
34
Q

Ankyrin has a ____ and is ____

A

Ankyrin has a wide cellular distribution and is the primary link between spectrin and band 3

(peripheral protein)

35
Q

Spectrin involves ___ and ___ subunits, self-associates into ___, and functions to ___ and ___

A

Spectrin involves alpha and beta subunits, self-associates into heterotramers, and functions to support lipid bilayer and regulate mobility of integral proteins

(peripheral protein)

36
Q

Band 3 plays a critical role in ___ and binds ___

A

Band 3 plays a critical role in Cl-/HCO3- exchange and binds cytoplasmic membrane components

(integral)

37
Q

Describe disruption of the RBC membrane

A

Disruption of the RBC membrane

38
Q

Determinants of intact RBC membrane are ____, ____, and ____

A

Determinants of intact RBC membrane are cell surface / volume ratio (most important), structural integrity, and deformability

39
Q

RBC surface loss results in ____, leading to ____, ____, ____, and ____

A

RBC surface loss results in membrane fragmentation, leading to spherocytes, poikilocytes, bite cells, and elliptocytes

40
Q

RBC volume gain results in ____, leading to ____

A

RBC volume gain results in increased membrane permeability, leading to stomatocytes

41
Q

RBC surface gain results in ____, leading to ____

A

RBC surface gain results in accretion of membrane lipid, leading to target cells

42
Q

RBC volume loss results in ____ and ____, leading to ____

A

RBC volume loss results in decreased Hb and increased membrane permeability, leading to target cells

43
Q

Describe hereditary spherocytosis

A

Hereditary spherocytosis

  • Most common inherited hemolytic anemia
  • Deficiency in membrane proteins leads to mechanical instability, membrane loss, and spheroid fragile RBCs
  • Autosomal dominant inheritance most of hte time
  • Ankyrin > spectrin > band 3 deficiency
44
Q

Describe the pathophysiology of hereditary spherocytosis

A

Pathophysiology of hereditary spherocytosis

  1. Spectrin / ankyrin deficient areas -> unsupported membrane OR band 3 deficient membrane -> clustered llpids
  2. Budding off of membrane
  3. Spherocytosis
  4. Increased splenci trapping
  5. Erythrostasis
  6. Hemolysis
45
Q

Describe clinical features of hereditary spherocytosis

A

Clinical features of hereditary spherocytosis

  • Positive family history
  • Neonatal hyperbilirubinemia
  • Varied phenotypic severity
  • Evidence of hemolysis: anemia, jaundice, reticulocytosis
  • Complications: gallstones, aplastic crisis (parvovirus), splenomegaly
46
Q

Describe diagnosis and treatment of hereditary spherocytosis

A

Diagnosis and treatment of hereditary spherocytosis

  • Peripheral smear
  • Lab features: variable anemia, reticulocytosis, elevated MCHC, elevated total bilirubin
  • Osmotic fragility test
  • Genetic testing
  • Treatment: supportive therapy, transfusions, and splenectomy
47
Q

Describe hereditary elliptocytosis

A

Hereditary elliptocytosis

  • Autosomal dominant
  • Causedby alpha or beta spectrin deficiency
  • Clinical heterogeneity: carrier state, severe form (hereditary pyropoikilocytosis)
48
Q

Describe Southeast Asian ovalocytosis

A

Southeast Asian ovalocytosis

  • Autosomal dominant
  • Caused by band 3 deficiency
  • Mild anemia despite marked RBC rigidity
49
Q

Pentose phosphate pathway generates ____

A

Pentose phosphate pathway generates reducing power (NADPH) against oxidative stress

  • Glucose-6-phosphate dehydrogenase plays a major role
50
Q

___ plays a major role in the pentose phosphate pathway

A

Glucose-6-phosphate dehydrogenase plays a major role in the pentose phosphate pathway

51
Q

Glycolysis (Embden-Meyerhof pathway) generates ____

A

Glycolysis (Embden-Meyerhof pathway) generates high-energy phosphates for ATP

  • Pyruvate kinase is major rate limiting enzyme
52
Q

____ is major rate limiting enzyme in glycolysis (Embden-Meyerhof pathway)

A

Pyruvate kinase is major rate limiting enzyme in glycolysis (Embden-Meyerhof pathway)

53
Q

Describe the pentose phosphate pathway

A

Pentose phosphate pathway

  1. Generation of reducing power
  2. Regeneration of reduced form of glutathione
  3. Reduction of oxygen radicals
54
Q

Describe glycolysis (Embden-Meyerhof pathway)

A

Glycolysis (Embden-Meyerhof pathway)

55
Q

Describe RBC enzymopathies

A

RBC enzymopathies

  • Associated with phenotypic variability
  • Lack of characteristic RBC changes at baseline
  • Causes chronic non-spherocytic hemolytic anemia
  • Degree of hemolysis dependent on importance of enzyme and residual function of variant enzyme
56
Q

Gd is located ____

A

Gd is located on long arm of X chromosome

  • Deficient expression in hemizyous males
  • Variable expression in heterozygous females
57
Q

G6PD enzyme is present in ____, ____, and activity is ____ and ____

A

G6PD enzyme is present in all cells, cannot be replaced in RBCs, and activity is age-dependent and higher in reticulocytes

58
Q

Structural changes in G6PD due to mutations affect ____ and ____

A

Structural changes in G6PD due to mutations affect catalytic function and in vivo stability

59
Q

In G6PD deficient RBCs, exogenous factors cause ___, ___, and ___

A

In G6PD deficient RBCs, exogenous factors cause decreased NADPH, decreased reduced form glutathione, and decreased protection from oxidative stress

60
Q

____, ____, and ____ are triggers of acute hemolytic anemia in G6PD deficiency

A

Medications, infection, and fava beans / other legumes are triggers of acute hemolytic anemia in G6PD deficiency

61
Q

Describe symptoms of acute hemolytic anemia due to G6PD deficiency

A

Symptoms of acute hemolytic anemia due to G6PD deficiency

  • Hemolysis
  • Fever
  • Abdominal nd back pain
  • Coca-cola urine
  • Jandice and pallor
  • Hepatosplenomegaly
  • Hypovolemic shock
62
Q

Describe lab findings of G6PD deficiency

A

G6PD deficiency lab findings

  • Normocytic anemia
  • Brisk reticulocytosis
  • Leukocytosis
  • Hyperbilirubinemia
  • Hemoglobinuria
  • Renal insufficiency
  • Low RBC G6PD deficiency
63
Q

Describe glycolytic enzymopathies

A

Glycolytic enzymopathies

  • Deficiencies in multiple enzymes in pathway
  • Grouped as CNSHA
  • Autosomal recessive inheritance
  • Normal peripheral smear
  • Normal osmotic fragility
  • Partial response to splenectomy
  • Diagnose by quantitative assays
64
Q

Pyruvate kinase deficiency has ___ inheritance and ___ mutations are most common

A

Pyruvate kinase deficiency has autosomal recessive inheritance and PKLR mutations are most common

  • Impairment in substrate kinetics, regulatory properties, and thermal stability
65
Q

Pyruvate kinase is important for ___ formation

A

Pyruvate kinase is important for ATP formation

  • Deficiency results in increased cation permeability, increased 2,3-DPG, and rightward shift of HbO2 dissociation curve
66
Q

Pyruvate kinase deficiency presents with ___, ___, ___, ___, and ___

A

Pyruvate kinase deficiency presents with anemia, jaundice, splenomegaly, gallstones, and leg ulcers

  • Hyperbilirubinemia common in newborns
67
Q

Describe deficiencies of the Embden-Meyerhof pathway

A

Deficiencies of the Embden-Meyerhof pathway

  • Autosomal dominant usually
  • Various degrees of non-spherocytic hemolytic anemia
  • Important enzyme deficiences: hexokinase, aldolase, glucose-6-phosphate isomerase, triosephosphate isomerase, phosphoglycerate kinase

Heme / Onc (41 decks)

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