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Heme / Onc > SM_251b: Thalassemia > Flashcards

SM_251b: Thalassemia Flashcards

1
Q

Thalassemias are ___

A

Thalassemias are inherited blood disorders cuased by mutations in beta globin that result in inability of body to produce globin

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2
Q

Globins are ____

A

Globins are key components of hemoglobin

  • Inability to make globin causes anemia
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3
Q

HbF is ___

A

HbF is alpha2-gamma2

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4
Q

HbA is ____

A

HbA is alpha2-beta2

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5
Q

HbA2 is ___

A

HbA2 is alpha2-delta2

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6
Q

Describe normal erythropoesis

A

Normal erythropoesis: erythroid precursor cells proliferate and differentiate into mature RBCs

  1. Early stage: EPO -> commited progenitor cells divide / differentiate into proerythroblasts (EPO-dependent)
  2. Late stage: cells further mature through series of normoblast stages until enucleation -> rectic, mature RBCs (not EPO-dependent)
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7
Q

Beta thalassemia occurs due to mutations on ___

A

Beta thalassemia occurs due to mutations on beta globin locus

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8
Q

DNA mutations in beta thalassemia ___ predict phenotype

A

DNA mutations in beta thalassemia do NOT predict phenotype

  • Suggests genetic modifiers affect disease severity
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9
Q

Beta thalassemia is defined ___

A

Beta thalassemia is defined operationally

  • ≤ 8 transfusions in last 12 months: thalassemia major
  • < 8 transfusions: thalassemia intermedia
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10
Q

Describe modifying genes in thalassemia

A

Modifying genes in thalassemia

  • Innate ability to produce HbF
  • Alpha globin genotype: alpha thalassemia reduces alpha globin excess, extra alpha globin genes enhance imbalance
  • Genes that encode alpha globin chaperones or protect against hemolysis: alpha hemoglobin stabilizing protein, chaperone heat shock protein 70
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11
Q

Hemoglobin E disease is common in ____ populations and involves ____

A

Hemoglobin E disease is common in Southeast Asian populations and involves a single amino acid substitution caused by a point mutation in the beta globin gene

  • Activates cryptic mRNA splice site, reduced beta globin production
  • Homozygous Hb E is associated with relatively benign clinical course: microcytosis with mild/no anemia, weakened alpha/beta interface and less stable under oxidative stress
  • Coinheritance of Hb E with beta thalassemia results in a condition with similar severity as beta thalassemia
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12
Q

Describe alpha thalassemia mutations and genotypes

A

Alpha thalassemia mutations and genotypes

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13
Q

Describe HbH disease

A

HbH disease

  • Caused by mutation affecting 3/4 alpha genes
  • Found in patients from Southeast Asia, Middle East, Mediterranean
  • Most often results from deletional mutations
  • Nondeletional: deletion of 2 genes from one allele with alpha thalassemia point mutations plus small insertion / deletion in one other alpha globin gene: more anemia, more symptomatic than deletional
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14
Q

Describe Hb Constant Spring

A

Hb Constant Spring

  • Caused by nondeletional mutation in alpha2 gene
  • High frequency among Southeast Asian
  • Defect results in elongation of 3’ mRNA sequences and is unstable
  • Homozygous HbCS clinical picture similar to HbH disease
  • Co-inheritance with deletion of two other alpha genes results in moderate to severe condition: HbH / Constant Spring
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15
Q

Beta thalassemia involves ___ erythropoiesis

A

Beta thalassemia involves ineffective erythropoiesis

  • Microcytic anemia despite hypercellular marrow
  • Elevated endogenous EPO and relative EPO-resistance
  • Extramedullary hematopoiesis and chronic hemolysis also contribute to phenotype
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16
Q

Describe pathophysiology of alpha thalassemia

A

Alpha thalassemia pathophysiology

  • Excess gamma-globin during fetal development forms gamma-4 tetramers (Hb Bart): nonfunctional, decreases after birth
  • Excess beta globin postnatally forms beta-4 tetramers (HbH): relatively unstable and nonfunction, intracellular RBC inclusion bodies
  • Intracellular globin chains precipitate -> ineffective erythropoiesis -> membrane dysfunction and local oxidative damage
  • Acute hemolysis is more prominent in alpha thalassemia and HbH disease compared to beta thalassemia
17
Q

Methods for diagnosis of thalassemia are ____, ____, ____, and ____

A

Methods for diagnosis of thalassemia are high performance liquid chromatography, hemoglobin electrophoresis, DNA analysis, and CBC

18
Q

High performance liquid chromatography allows for ___

A

High performance liquid chromatography allows for efficient reproductible separation of normal and common abnormal globin variants

19
Q

Describe hemoglobin electrophoresis

A

Hemoglobin electrophoresis

  • Separation of normal and most common abnormal globin variants
  • Performed at both alkaline and acid pH
  • Cannot quantify HbA2
  • Test used for confirmatory testing for beta globin defects
20
Q

Diagnostic criteria for thalassemia ___ beyond infancy

A

Diagnostic criteria for thalassemia change beyond infancy

21
Q

Thalassemia peripheral blood smear involves ___ with marked ___ and ___

A

Thalassemia peripheral blood smear involves microcytic hypochromic anemia with marked anisocytosis and poikylocytosis

  • RBC changes in thalassemia due to ineffective erythropoeisis and hemolysis
22
Q

Describe clinical features of beta thalassemia

A

Beta thalassemia clinical features

  • Poor growth
  • Thal facies
  • Jaundice, hyperpigmented skin
  • Hepatosplenomegaly
  • Endocrine dysfunction
  • Cardiomyopathy
  • Bony deformities, increased fracture risk
23
Q

Optimal thalassemia care balances ___ with ___

A

Optimal thalassemia care balances appropriate transfusion support with adequate iron chelation

  • Complications in thalassemia often result from an inability to do one or both
24
Q

Describe clinical features of alpha thalassemia

A

Alpha thalassemia clinical features

  • Usually results in fetal demise
  • HbH hydrops fetalis: typically due to nondeletional mutation of alpha 2 globin gene plus deletion of both alpha genes from other allele
  • Survival depends on intrauterine diagnosis and intervention
  • Associated with neurocognitive deficits, limb abnormalities, and hepatomegaly with persistent fetal hematopoiesis in the liver
25
Q

Describe HbH clinical features

A

HbH clinical features

  • Iron overload
  • Hepatosplenomegaly
  • Cholelithiasis
  • Increased anemia during pregnancy
26
Q

Thalassemia treatment involves ____, ____, ____, and ____

A

Thalassemia treatment involves chronic transfusions, iron chelation, splenectomy, and bone marrow / stem cell transplantation

27
Q

Clinical spectrum of thalassemias ranges from ___ to ___

A

Clinical spectrum of thalassemias ranges from non-transfusion dependent thalassemias to transfusion-dependent thalassemia

28
Q

Describe considerations in initiating transfusions for thalassemia

A

Considerations in initiating transfusions for thalassemia

  • Consistent low hemoglobin (anemia)
  • Growth issues: important to monitor in thal intermedia
  • Bony changes: transfusions can slow and potentially reverse
  • Transfusion-related complications: blood borne pathogens, transfusion reactions, RBC antibody formation
29
Q

Describe monitoring iron overload in thalassemia

A

Monitoring iron overload in thalassemia

  • Serum ferritin concentration
  • Liver iron content: better reflection of total body iron burden
30
Q

Describe goals for iron chelation therapy in thalassemia

A

Goals for iron chelation therapy in thalassemia

  • Prevent accumulation of harmful levels of iron
  • Prevent tissue injury from labile iron pool
  • Reduce morbidity and mortality associated with iron overload
  • Minimize toxicity of excess chelation
  • DFO, deferiprone, deferasirox
31
Q

Describe curative therapies for thalassemia

A

Curative therapies for thalassemia

  • Hematopoietic stem cell transplant: standard care stem cell transplant with HLA-matched sibling donors
  • Gene therapy
  • Gene editing
  • Reprogrammed stem cells
32
Q

___ may promote transfusion independence in transfusion-dependent beta thalassemia

A

LentiGlobin may promote transfusion independence in transfusion-dependent beta thalassemia

Heme / Onc (41 decks)

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