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CPR 2 > Blood Disorders > Flashcards

Blood Disorders Flashcards

1
Q

Where are the a-chains genes located

A

Chromosome 16

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2
Q

Where are B chain genes located?

A

Chromosome 11

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3
Q

What forms different hemoglobin genes?

A

Various hemoglobin species formed throughout development from these genes

2 a-globin genes (HBA1 & HBA2); (a1 and a2) (4 a-globin genes in normal individual)

1 B globin gene (HBB; 2 B-globin genes in normal individual

Zeta and epsilon (embryonic globin chains)

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4
Q

What is the composition of hemoglobin ?

A

HbA- 90-95%

HbF- 1-2%

HbA2- 2-3%

All hemoglobins consist of two different pairs of globin chains with gene

Embryonic hemoglobins have zeta chains and epsilon chains

Fetal hemoglobin (HbF): 2a chains and 2y chains (a2y2)

In adults, hemoglobin A (a2B2) and hemoglobin A2(a2delta2)

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5
Q

What are hemoglobinopathies?

A

Genetic disorders caused by production of structurally abnormal hemoglobin or by synthesis of insufficient amounts of normal hemoglobin

Hundreds of mutations known, but we shall look at four of these in detail

Hemoglobinopathies—> Qualitative change: mutation in nucleotide sequence sequence of globin chain

Thalassemia—> quantitative change: decreased or absent globin chain synthesis

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6
Q

What is hemoglobin S?

A

Single point mutation in B-globin gene (HBB) on 6th codon

  • glutamic acid substituted by valine at position 6 of B-globin chain
  • HbS moves slower to anode than HbA in electrophoresis
  • Homoxygous inheritance (HbSS) causes sickle cell disease
    • NO production of HbA
  • Autosomal recessive disorder
  • Painful episodes ‘sickle cell crisis’ and hemolytic anemia
  • Reduced life span of RBCs
  • Are there manifestations of sickle cell anemia during fetal life???

Hydrophobic ‘sticky’ patch in HbS(Glu—> Val)

Poorly solubility in deoxycytidine state

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7
Q

What are the symptoms of sickle cell anemia?

A

Painful crisis caused by anemia, hemolysis and vaso-occlusive ischemia in abdomen and long bones

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8
Q

How is HbS treated?

A

-Methylation of CG in promoters represses fetal globin (y) transcription after birth

  • Drugs increase fetal globin (y) expression:
    • 5-azacytidine (Decitabine; demethylating agent)
    • Hydroxyurea, butyrate compounds (inhibit histone deacetylation)

-Alter Epigenetic gene regulation and change histone acetylation —> switching on y-globin synthesis —> ‘depression’ of y-globin gene—> more HbF formation

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9
Q

How does hydroxyurea help HbS?

A

HbF inducers

Effect of hydroxyurea: inhibit HbS polymerization by increasing HbF levels

Mixed hybrid a2B^sy less likely to polymerize than hemoglobin S

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10
Q

Explain inheritance of sickle cell trait

A

Heterozygote (HbAS) sickle cell trait (1 normal B-globin gene and 1-B^s globin gene)

  • Produce both normal and abnormal hemoglobin
  • generally benign
  • develop sickle cell crisis in low oxygen saturation
    • Deep sea diving and unpressurized aircraft
    • Extreme exercise such as army training
  • Africa, Mediterranean basin, Middle East and India
    • high carrier frequency

-Heterozygotes- survival advantage (Heterozygote advantage ) against falciparum malaria

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11
Q

Explain the pathology of Hemoglobin C

A
  • Point mutation 6th codon of B-globin gene (HBB gene)—> missense mutation (Glu—> Lys)
  • HbC moves slowest to anode (positively charged electrode) on hemoglobin electrophoresis
  • HbC homozygotes have mild hemolysis
  • HbC- Lower solubility than HbA
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12
Q

What is HbSC?

A

Two different mutations of B-globin gene

One B-globin gene has ‘S’ mutation and other ‘C’ mutation

HbSC: Sickling episodes similar to sickle cell disease (milder)

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13
Q

How can HbS, HbSC and HbAaS be diagnosed?

A

ASO & RFLP

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14
Q

What are the types of thalassemia?

A

Reduced globin chain synthesis

  • Alpha thalassemia-reduced alpha chain synthesis
  • Beta thalassemia- reduced beta chain synthesis

Imbalance in Alpha:Beta chain ratio
-Normal ratio is 1:1

Thalassemia (Greek): thalassemia (sea) and haima (blood)

South east Asia, Africa, Mediterranean

Heterozygotes protected against malaria

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15
Q

Describe thalassemia

A

Reduced a-globin chain synthesis
-Relative excess of beta globin or gamma globin chains

Deletion of entire a-globin gene
-Unequal cross-over during homologous recombination

2 a-globin genes: 4 copies of a-globin genes (HBA1 and HBA2)
-Complex inheritance

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16
Q

What can gene duplication result in?

A

Gene duplication during evolution may result in insertions and deletions of gene copies due to unequal crossover during meiosis

Loss of one gene (as/ a-): silent carrier)

Loss of two gebes: (a-/a-): mild anemia

Loss of three gebes: (a-/- -) B4 tetramer (HbH), moderate hemolytic anemia

Loss of all a goon is lethal (- -/- -): hydros fetalis

17
Q

What are the two forms of a-thalassemia?

A 
Two forms:
Hydrops fetalis (Hb Bart)

Hemoglobin H disease

Carrier: deletion of two a-globin genes

  • aa/ - -: in Cis configuration of
  • a -/ - a in trans configuration
18
Q

What is Hemoglobin Bart hydrops fetalis (Hb Bart) syndrome?

A

Most severe form of a-thalassemia

Hb Bart: Aggregation of y4 tetramers (due to absence of a-globin chains)

Fetal onset of generalized edema, ascites, pleural and pericardial effusions, and severe anemia

Stillbirth or death in neonatal period

All four a-globin alleles deleted (inactivated)

No detectable HbF or HbA

19
Q

What is Hemoglobin H (HbH)?

A

Presents in infancy or childhood

Mild to moderate microcytic hypochromic hemolytic anemia

Hepatosplenomegaly

Mild thalassemia-like bone changes may be present

HbH: Aggregation of B4 tetramers (deficiency of a-globin chains)
-May also have some HbBart (aggregation of y4 tetramers)

Deletion of three of four a-globin alleles

HbA levels may be low; or low normal

20
Q

Explain the inheritance of B-thalassemia

A

Autosomal recessive inheritance

Different mutations of beta-globin gene (allelic heterogeneity)

Compound heterozygotes (HBB gene)

Variable severity disorder

Types of beta globin mutation

B+ mutation: reduced gene expression

Bo mutation: complete suppression of gene expression

Absent or reduced synthesis of B-globin chains of Hb

Excessive a-globin precipitate and severe hemolytic anemia

  • excessive a-globin chains bind to RBC membranes causing membrane damage
  • Form toxic aggregates resulting in hemolysis
    - (Remember: they do not form tetramers )
21
Q

What are the 3 forms of B-thalassemia?

A

B thalassemia major

B thalassemia intermedia

B thalassemia minor

22
Q

What is B thalassemia major?

A

This is Cooleys anemia or Mediterranean anemia

Homozygotes or compound Heterozygotes for Bo or B+ gebes

Two severe mutations

Very low or absent HbA levels- Absent or very little B globin dynthesis

High HbA2 and HbF levels (compensatory)

23
Q

What is B-thalassemia intermedia?

A
  • Homozygotes or compound Heterozygotes (different B+ mutations)
  • One severe mutation, second mutation less severe or two less severe mutations
  • Low HbA levels- Some B globin synthesis
  • High HbA2 and HbF levels (compensatory)
24
Q

What is B-thalassemia minor?

A

Carrier or trait or Heterozygotes

  • Heterozygotes (one normal and one mutant B-globin gene)
  • Almost normal HbA levels
25
Q

Explain alleilic heterogeneity of B-thalassemia

A

Over 200 disease causing mutations

Point mutations, frameshift mutations, splice site mutations, promoter mutations in B-globin gene (HBB gene)

Allelic heterogeneity: different mutations in same gene

26
Q

Explain the effect of prenatal diagnosis and carrier screening

A
  • Carrier screening in Mediterranean populations
  • Ethical concerns about termination of pregnancy and forced participation have been balanced against severity of conditions
  • Screening successful in reducing incidence of disorder

High carrier frequency in Mediterranean, North America and Middle East

Decline in thalassemia in various populations after initiation of prenatal diagnosis in 1972

27
Q

How does bone change in thalassemia?

A

More common in beta thalassemia; may be seen in alpha-thalassemia

Frontal blossing, malar prominence: indicate Extramedullary erythropoiesis

Bone marrow tries to compensate and expands to perform erythropoiesis And leads to bone deformity and fractures; Erythopoiesis in flat bones is stimulated (extramedullary erythopoiesis)

28
Q

How is B-thalassemia managed?

A

Bo homozygotes (thalassemia major) present at about six months- 2 years as expression of y-globin gebes decreases

Regular transfusions correct anemia and suppress erythopoiesis, but lead to iron deposition
-Iron chelation and dietary control to manage composition

Bone marrow transplantation from HLA-identical sibling

29
Q

What is the significance of hemophilia A and B?

A
  • X linked recessive, bleeding disorders
    • Deficiency of factor VIII(Hemophilia A)
    • Factor IX(hemophilia B)
  • Hemorhage into joints and muscles, easy bruising, and prolonged bleeding from wounds
  • Hemophilia A and B clinically similar
    • Distinguished by assays of factor 8 and 9
    • prolonged APTT; PT:normal ; bleeding time :normal

8ncidence:

  • 1 in 5,000-10000 male births for hemophilia A
  • 1 in 50,000 male births for hemophilia B
30
Q

What are the genes involved in hemophilia?

A

Genes for factor VIII and factor 9 located on X-chromosome

Gene for factor 8 is unusually large

- Intron inversion (40%) that disrupts F8 gene
- Deletions, insertions, and point mutations (50-60%)
- Allelic heterogeneity

Factor 9 gene
-point mutations and deletions

31
Q

How do intron inversions lead to hemophilia A?

A

Repeat sequences on same chromosome misalign aberrantly and then recombination occurs

32
Q

What is the inheritance pattern of hemophilia?

A

Inheritance is Affected male—> carrier affected male

No male to male transmission. A son cannot inherit mutant allele from his father

Carrier mother has 50% chance of passing the faulty X-chromosome to her daughter

Affected father always passes on affected gene to all his daughters (obligate carriers)

33
Q

How do females exhibit hemophilia?

A

Usually asymptomatic since random X inactivation/Lyonization results in appropriately equal proportions of somatic cells in which either normal X or mutant X chromosome is active, and clotting factor synthesis is adequate for hemostasis

Some carrier females have increased bleeding tendency (manifesting heterozygote)
-Due to skewed X-chromosome inactivation leading to a higher percentage of inactivation of normal X-chromosome

34
Q

How is Hemophilia treated?

A

Recombinant factor 8 or 9 replacement therapy
-Antibodies against recombinant protein in about 10% of patients

Hemophiliacs received clotting factor from pooled blood

  • Risk of HIV and hepatitis B and C via contaminated blood (as donor blood was not rigorously screened)
  • More than 50% of hemophiliacs contracted HIV/ hepatitis from transfusion of infected blood (before testing for HIV was routinely practiced)

CPR 2 (32 decks)

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