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HemOnc > 10 - Hemoglobinopathies and Thalassemias > Flashcards

10 - Hemoglobinopathies and Thalassemias Flashcards

1
Q

Normal Hemoglobin

A

Post-embryonic hemoglobins:
contain two pairs of polypeptide
chains
* Alpha
* Non-alpha
* Beta (α2β2: HbA) – makes up
most of adult Hb
* Gamma (α2γ2: HbF) – fetal Hb
* Delta (α2δ2: HbA2) – minor
adult Hb; 2.5%

  • Makes up a four subunit,
    allosteric molecule
  • Conformation and O2 affinity
    changes as each successive O2
    molecule is bound
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2
Q

States of normal hemoglobin

A
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3
Q

proportion of globin chains from prenatal to 1 yo

A
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4
Q

Chromosomal location of globin chains

A
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5
Q

O2 hemoglobin dissociation curve

A
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6
Q

Hemoglobin disorder types

A

Quantitative disorders (Thalassemias)
* Result from the decreased and imbalanced production of structurally
normal globins
* Imbalances in the production of α and β chains leads to damage of RBCs
and RBC precursors in the bone marrow

Qualitative disorders
* Arise from point mutations that change the amino acid sequence of the
globin, thereby leading to functional changes in the hemoglobin
* Decreased solubility (HbS)
* Instability
* Altered O2 affinity
* Altered maintenance of the oxidation state of heme iron

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7
Q

The Evolution of Hemoglobin Disorders

A
  • Tend to occur in higher frequency in geographic
    regions endemic for falciparum malaria – survival
    advantage
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8
Q

Alpha thalassemias – Genetic Nomenclature

QUANTITATIVE DISORDERS OF HEMOGLOBIN

A
  • SE Asia and W Africa
  • Chromosome 16 – 2 genes present; more heterogenous
    presentations
  • (α α/ α-): Silent carrier; no anemia, no morphologic abnormalities
  • (α α/–) or (α -/ α -): α thalassemia trait; mild microcytic anemia
  • Tetrameric Hemoglobins
  • (α -/–): α thalassemia major
  • (–/–): Hydrops fetalis
  • 4 Υ Hgb Bart
  • 4 β Hgb H – precipitates into Heinz bodies
  • May not see changes on hemoglobin electrophoresis
  • Generally you will need mutation analysis for diagnosis
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9
Q

Alpha thalassemia

QUANTITATIVE DISORDERS OF HEMOGLOBIN

A
  • Genotypes:
  • (αα/–)
  • (α-/α-)
  • Trans v cis
  • Lifelong microcytosis with mild anemia
  • Target cells on peripheral smear
  • Importance of genetic counseling
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10
Q

Alpha thalassemia (intermedia / major)

QUANTITATIVE DISORDERS OF HEMOGLOBIN

A
  • Genotype: (α -/–) leads to four beta chains (HbH)
  • Hg H is unstable and precipitates as the RBC ages, forming Heinz bodies,
    which causes bite cells and a hemolytic anemia
  • Variable presentation
  • Some can present like thal-intermedia – occasionally need transfusions,
    moderate anemia
  • Some can present like thal-major
  • Splenomegaly
  • Hb 7-11 g/dl
  • Low MCV and MCH, high RDW
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11
Q

Alpha thalassemia major

QUANTITATIVE DISORDERS OF HEMOGLOBIN

A
  • Genotype: (–/–) leads to four
    gamma chains (Hb Bart;
    Hydrops fetalis)
  • All four genes affected – no alpha chains
    form
  • Severe anemia, high output heart failure
    → hydrops fetalis (generalized edema,
    “water laden fetus”)
  • Marked hepatosplenomegaly
  • Anistocytosis, poikilocytosis
  • Intrauterine death, followed by stillbirth
    at 25-40 weeks
  • Can be treated in utero by exchange
    transfusions
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12
Q

Beta Thalassemias – Genetic Nomenclature

QUANTITATIVE DISORDERS OF HEMOGLOBIN

A
  • Southern Europe, SE Asia, Africa, Middle East
  • β thalassemias result from >200 mutations in the beta
    globin gene
  • Chromosome 11
  • Normal beta gene synthesis: β/ β
  • Complete absence of beta gene synthesis: β0
  • β0/β0: Cooley’s anemia – β Thalassemia major
  • Decreased but not absent beta gene synthesis: β+
  • See changes on hemoglobin electrophoresis
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13
Q

Beta thalassemia major

QUANTITATIVE DISORDERS OF HEMOGLOBIN

A
  • Absence or severe deficiency of beta globin synthesis
  • Symptoms usually evident at 6-12 mos
  • Genotypes:
  • (β0/ β0)
  • (β0/ β+)
  • Leads to four alpha chains – very unstable
  • Moderate to severe lifelong anemia requiring transfusions
  • Increased HbF → impaired oxygen delivery to tissue
  • Iron overload
  • Transfusions
  • Iron hyperabsorption from the gut
  • Growth retardation
  • Ineffective erythropoiesis → extramedullary erythropoiesis
  • Leads to facial abnormalities: frontal bossing, maxillary prominence
  • Hepatosplenomegaly
  • Prone to infection
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14
Q

Beta thalassemia major - Lab findings

A
  • Microcytic, hypochromic RBCs
  • Marked anistocytosis, poikilocytosis
  • Target cells - Nucleated
    red blood cells

Poikilocytosis generally refers to an increase in abnormal-shaped red blood cells that make up 10% or more of the total red blood cells

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15
Q

Beta thalassemia major - Complications

A
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16
Q

QUALITATIVE DISORDERS OF HEMOGLOBIN

A

Hemoglobin S (HbS):
Mutation: HbS results from a mutation in the beta-globin gene, leading to the substitution of glutamic acid with valine at the sixth position of the beta-globin chain.
Clinical Significance: Individuals with two copies of the HbS gene have sickle cell anemia, a genetic disorder characterized by misshaped (sickle-shaped) red blood cells. This can lead to various complications, including pain, anemia, and organ damage.

Hemoglobin E (HbE):
    Mutation: HbE is caused by a mutation in the beta-globin gene, resulting in the substitution of glutamic acid with lysine at the 26th position of the beta-globin chain.
    Clinical Significance: HbE is usually found in individuals of Southeast Asian descent. While having one copy of the HbE gene may not cause significant health problems, having two copies (HbE/HbE) can lead to a mild form of beta-thalassemia, a blood disorder characterized by reduced production of hemoglobin.

Hemoglobin C (HbC):
    Mutation: HbC is the result of a mutation in the beta-globin gene, leading to the substitution of glutamic acid with lysine at the sixth position of the beta-globin chain.
    Clinical Significance: HbC trait (heterozygous) individuals usually do not experience severe health problems. However, individuals with two copies of the HbC gene may have hemoglobin C disease, a condition characterized by mild hemolytic anemia and enlarged spleen.
17
Q

Phenotypes caused by Hgb S,E,C variants

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • More severe
    phenotype
    – HbSS: sickle cell
    anemia
    – HbSC: SC disease
    – Sickle β thalassemia
  • HbS β0
  • HbS β+
  • Less severe phenotype
    – HbAS: sickle cell trait
    – HbC disease
    – HbE disease
18
Q

Hemoglobin S

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Occurs due to a point
    mutation: Glu 6Val
  • Sixth amino acid in β chain is changed from glutamine (hydrophilic) to valine (hydrophobic)
  • Leads to different electrophoretic mobility
  • Deoxy-HbS: 50 times less soluble than deoxy-HbA
  • Homozygous: HbSS
  • Heterozygous: HbAS
    (sickle trait)
  • Chromosome 11
19
Q

Sickle Cell trait demographics

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • 1 in 12 African-Americans carry sickle cell trait (heterozygous)
  • 1 in 500 African-American births have a homozygous mutation
  • 1 in 300 African-American births are SS,
    SC, or S/Bthal
  • 1 in 1000-5000 Hispanic-American births
  • Also found in middle East, Mediterranean, Southern India
20
Q

Hemoglobin E

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Second most common Hb variant (after HbS)
  • Substitution of glutamic acid by lysine at the 26th
    position of the beta chain
  • Single-base substitution creates a cryptic splicing site → abnormal mRNA processing and reduction of mRNA that can be translated
  • Sometimes referred to as a “thalassemic hemoglobinopathy” – decreased beta chain production
  • Highest frequency in South and SE Asia about 10% ofthe population.
  • Can have co-inheritance with HbS or genes involved in beta thalassemia.
21
Q

Hemoglobin E syndromes

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Heterozygotes: HbAE (HbE trait)
  • Asymptomatic; may or may not have mild anemia
  • May have normal smear or may have hypochromia, microcytosis,
    target cells, basophilic stippling
  • Homozygotes: HbEE
  • Asymptomatic with no overt hemolysis or splenomegaly
  • Mild anemia, microcytosis (MCV 65-70), reduced MCH
  • Peripheral smear with hypochromia, microcytosis, variable target
    cells, irregularly contracted cells
  • HbE and HbA2 makes up 85-99% of total hemoglobin
22
Q

Hemoglobin C

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Third most common mutant Hb
  • Substitution of glutamic acid with lysine at the sixth
    position on the beta globin chain
  • Decreased solubility in the deoxy and oxy forms – undergoes
    intraerythrocytic aggregation and crystal formation
  • Dehydrated and poorly deformable RBCs – get trapped in the spleen
  • Occurs in 2-3% of African-Americans
  • Important: on Hb electrophoresis, comigrates with
    HbA2, HbE and HbOarab
  • Need citrate gel electrophoresis or high-performance liquid
    chromatography (HPLC)
  • Can have co-inheritance with HbS, beta thalassemia
    genes
23
Q

Hemoglobin C syndromes

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Heterozygotes: HbAC (Hb C trait)
  • Clinically normal
  • Normal hemoglobin, may have microcytosis
  • Peripheral smear may be normal or show microcytosis and target cells
  • Homozygotes: HbCC
  • Mild hemolytic anemia, microcytosis, slight reticulocytosis
  • Elevated MCHC
  • On peripheral smear, see prominent target cells, microcytosis, irregularly
    contracted RBCs
  • Usually not very symptomatic
24
Q

Hgb Constant Spring (hgb CS)

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Mutation at the termination codon of α2-globin
  • This leads to synthesis of unstable and elongated α2-globin chains with 172 instead of 141 amino acid
    residues.
  • Homozygotes present clinically like α-thal intermedia
  • Found almost exclusively in people from Southeast
    Asia and China
  • Typing:
  • CS trait: CS 1%
  • CS homozygous: CS 5%
  • CS/αthal: looks clinically like Hgb H (3 gene deletions), CS 3-5%
25
Q

Sickle cell disease syndromes

QUALITATIVE DISORDERS OF HEMOGLOBIN

A

Sickle cell disease can be due to 3 genotypes:
* HbSS (Sickle cell anemia)
* HbSC (SC disease)
* Sickle β Thalassemia
* HbSβ0: do not make any normal HbA – clinically
indistinguishable from SS
* HbSβ+: can make some HbA – clinically more mild
than SS

26
Q

Sickle cell anemia

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Hematologic manifestations
  • Anemia
  • Typically NOT microcytic
  • If microcytosis, think about concomitant iron deficiency or thalassemia
  • Leukocytosis, thrombocytosis
  • Howell-Jolly bodies (asplenia)
  • Reticulocytosis
  • Anisocytosis, poikilocytosis
  • Increased risk for thrombosis
  • 12% of HbSS pts have a VTE by age 40
  • Other lab features
  • Increased LDH
  • Decreased haptoglobin
  • Increased reticulocytes, increased indirect bilirubin
27
Q

Sickle cell crises

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Painful vaso-occlusive crisis
  • Aplastic crisis
  • Parvovirus infection of RBC precursors → low reticulocyte count with
    rapidly decreasing Hb
  • Acute Chest Syndrome
  • Hyperhemolytic crisis
  • Delayed hemolytic transfusion reaction
  • Transfused cells and the patient’s own cells are hemolyzed (“bystander
    hemolysis”)
  • Splenic or hepatic sequestration crisis
  • Can occur in children prior to splenic infarction
  • Can occur in adults with SC disease
  • Profound anemia, massive splenomegaly, hypovolemic shock
28
Q

Sickle cell anemia – organ involvement

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
29
Q

Acute chest syndrome

QUALITATIVE DISORDERS OF HEMOGLOBIN

A

Acute chest syndrome
* Most common cause of death
* Second most common cause of hospitalization
* CLINICAL diagnosis
* Fever * Cough * Chest pain * Hypoxia * New infiltrate on CXR * Treatment * RBC exchange transfusion * O2, antibiotics, prevention
(incentive spirometry)

30
Q

Sickle cell anemia – long-term management

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Vaccinations: pneumococcal, meningococcal, H influenza
  • Folate 1 mg daily (unless deficiency documented) – may be on examinations but no longer SOC
  • Annual eye exams
  • Hydroxyurea
  • Increases HbF, decreases WBC, increases cell size
  • Decreases stroke, pain, acute chest and increases survival
  • Crizanlizumab (Adakveo)
  • Inhibits P-selectin adhesion
  • FDA approved to decrease pain VOCs by 50% but not in the EU
  • Voxelotor (Oxbryta)
  • Stabilizes the deoxygenated Hgb molecule and prevents polymerization
  • FDA approved to improve anemia
31
Q

Sickle cell anemia – long-term management

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Simple Transfusions
  • To optimize before surgery and before delivery in pregnancy
  • Exchange transfusions
  • Acute chest syndrome
  • Acute stroke
  • Priapism
  • Chelation therapy for iron overload
  • Allogeneic bone marrow transplant
  • Gene therapy
  • Various
  • Lyfgenia - Autologous transplant of stem and progenitor cells transduced with
    BB305 lentiviral vector encoding a modified β globin gene (lovotibeglogene
    autotemcel)]
  • Casgevy – CRISPR targets BCL11A which allows increased production of the non-
    alpha globin Υ and therefore Hgb F(exagamglogene autotemcel)
32
Q

SC disease

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • Hb electrophoresis: 50% HbS, 50% HbC (runs as HbA2)
  • Less anemic than HbSS patients – 20% normal HCT
  • Presence of HbC leads to more intracellular
    dehydration, worsened sickling and hyperviscosity
  • Clinical features:
  • Splenomegaly
  • More ocular and bone complications
  • Typically live longer than patients with HbSS
33
Q

Sickle Cell - Beta Thalassemia

QUALITATIVE DISORDERS OF HEMOGLOBIN

A
  • HbSβ0: do not make any normal HbA –
    clinically indistinguishable from SS
  • HbSβ+: can make some HbA – clinically
    more mild than SS
34
Q

Summary of QUALITATIVE DISORDERS OF HEMOGLOBIN

A
35
Q

Sickle cell trait

A
  • 8-9% of the African-American population
  • Generally symptomatic
  • Rare complications
  • Renal papillary necrosis
  • Hematuria
  • Renal medullary carcinoma
  • HbA to HbS ratio of 60%:40%
  • Altered gene has decreased function
36
Q

Conclusions for hemoglobinopathies and thalassemias

A
  • Normal structure and function of hemoglobin is
    imperative for gas exchange and delivery of O2 to
    tissues
  • Changes in hemoglobin structure and production leads to various pathology.
  • Thalassemias are due to imbalanced globin chain synthesis (quantitative problem)
  • Can be transfusion dependent and transfusion independent
  • Can involve genes responsible for the alpha or beta globin chains
  • Hemoglobinopathies are usually due to mutations in the beta globin chain which leads to altered hemoglobin structure and function.
    (qualitative problem)
  • Genes can be co-inherited (ie compound heterozygous) which can
    lead to different phenotypes!

HemOnc (29 decks)

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