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Heme/Lymph > Hemoglobinopathy > Flashcards

Hemoglobinopathy Flashcards

1
Q

What are the broad classifications of Hb disorders?

A
  • Structural variants
    • Abnormal globin chain structure due to globin gene mutation
    • Varied clinical effects depending on location and nature of mutation in globin chains
  • Thalassemias
    • Under-production of structurally normal globin chains
    • Generally microcytic/hypochromic anemias of varying severity
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2
Q
  • What are the normal hemoglobins?
  • Which one dominates during fetal life?
  • What are the expected values for Hb in an adult?
A
  • Three normal hemogobin species in fetal and postnatal life
    • Hemolobin A: (α2β2)
    • Hemoglobin F: (α2γ2)
    • Hemoglobin A2: (α2δ2)
  • Hemoglobin F dominates during fetal life
  • Normal adult complement (achieved after 6 months to 1 year of age)
    • HbA: 96%
    • Hb F: 1%
    • Hb A2: 3%
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3
Q

Abnormal hemoglobins

A
  • More than 500 structural hemoglobin variants have been described
    • Most are single amino acid replacements in globin molecules (due to single base pair substitutions in globin genes)
    • Any globin gene may be affected
    • Occasional other types of mutations
  • 15 variants with 2 amino acids replaced
    • Deletions
    • Insertions
    • Chain elongation
    • Fusion genes
  • Most clinically silent
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4
Q

Hb Structural Abnormalities:

  • Depends On:
  • **Potential Consequences: **
A
  • Depends on:
    • What globin gene is affected
      • e.g, delta gene mutations are clinically inconsequential
    • Location of substitution in the tertiary structure and/or quaternary stuctures of the globin or hemoglobin molecules
  • Potential consequences:
    • Sickling
    • Instability
    • Altered oxygen affinity (increased or decreased)
    • Increased susceptibility to oxidation to methemoglobin
    • Under-production
    • Various combinations of the above
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5
Q

What lab techniques are used to diagnose hemoglobinopathies?

A
  • Hemoglobin electrophoresis
    • Gel
    • Capillary
  • High performance liquid chromatography (HPLC)
  • Other advanced techniques
    • Isoelectric focusing
    • Globin chain electrophoresis
    • Gene mutation analysis
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6
Q
  • How is routine electrophoresis typically performed?
  • What is the isoelectric point of HbA?
  • What does the migration of other hemoglobins depend on?
A
  • Typically performed in parallel with alkaline and acid buffers
  • HbA has isoelectric point of 6.8
    • Negative charge in alkaline buffers ⇒ migrates toward anode (+)
    • Positive charge in acid buffers ⇒ migrates toward cathode (-)
  • Migration of other hemoglobins depends on:
    • Net charge in alkaline electrophoresis
    • Net charge and interaction with components of media in acid electrophoresis
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7
Q

What are the two methods of HPLC?

A
  • Fully automated cation exchange chromatography method
  • Whole blood method (whole blood hemolysate)
    • Hemoglobins adsorbed onto resin particles in column
    • Different species differentially eluted based on affinity for resin by gradually changing ionic strength of elution buffer
    • Hemoglobins come off the column at highly predictable retention times
      • Some correlation with migration on alkaline electrophoresis
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8
Q
  • Define sickle cell disease:
  • What causes SCD?
  • Which type of HbS protects against malaria?
  • What is the frequency of homozygous S?
A
  • Homozygous abnormality of the beta globin chain
  • Glu to Val substitution at amino acid 6 of β-chain (β6Val)
  • Heterozygous HbS (S-trait) confers protection against malaria
    • 4% allelic frequency for Hb S gene among African-Americans
    • Rare in other ethnic groups
  • Homozygous S occurs at a frequency of 1 in 600 in African Americans
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9
Q

Sickle Cell Disease (SS)

Pathophysiology

A
  • Deoxygenated HbS forms long polymers that distort the shape of the cell into an elongated, sickled form
    • Intermolecular contacts involve abnormal valine at amino acid 6
  • Extent of HbS polymerization is time and concentration dependent
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10
Q

What factors affect HbS concentration?

A
  • Percentage of hemoglobin S of total hemoglobin
    • Homozygous versus heterozygous
    • Presence of other hemoglobin species (e.g., Hb F)
  • Total hemoglobin concentration in the red cells (MCHC)
    • Increased in states of cellular dehydration
    • Decreased when there is co-existent thalassemia
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11
Q

How is sickling of RBCs time dependent?

A
  • Importance of transit time of red cells through low oxygen tension microvasculature
  • Sickling enhanced in anatomic sites with sluggish flow (e.g., spleen and bone marrow)
  • Blood flow through microvasculature retarded in certain pathologic states
    • Inflammation
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12
Q

What clinical settings are predisposing to sickling of RBCs?

A
  • Hypoxia
  • Acidosis
    • Shift of oxygen dissociation curve to right, causing increased deoxygenation of Hb S
  • Dehydration
    • Hypertonicity causing RBC dehydration
  • Cold temperatures
    • Probably as a result of peripheral vasoconstriction with resultant sluggish flow
  • Infections (multiple mechanisms)
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13
Q

SCD Pathophysiology:

  • At what pressure do RBCs begin to sickle?
  • Is sickling reversible?
  • What happens to RBC lifespan?
A
  • SS cells begin to sickle at ~40mm Hg
  • Sickling is initially a reversible process, but after multiple sickling/unsickling cycles, membrane damage produces an irreversibly sickled cell
  • RBC lifespan decreased to 20 days
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14
Q
  1. What are the long term effects of sickling?
  2. Which of these correlates with irreversibly sickled cells?
  3. Which of these correlates with “stickiness”?
A
  • Chronic hemolysis
    • Correlates with the number of irreversibly sickled cells
  • Microvascular occlusion with resultant tissue hypoxia and infarction
    • Does not correlate with irreversibly sickled cells
    • Related to increased “stickiness” of SS red cells because of membrane damage
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15
Q

When do clinical manifestations of SCD begin to appear?

A
  • Newborns clinically fine because of high HbF levels
  • Hematologic manifestations begin by 10-12 weeks of age
  • Clinical severity variable from patient to patient
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16
Q

What are the major complications of SCD?

A
  • Severe anemia
  • Acute pain crises
    • Result from vaso-occlusion, particularly in marrow
    • Major cause of ED visits and hospital admissions
  • Auto-splenectomy
  • Acute chest syndrome
  • Strokes
    • Risk of stroke of 11% by age 20
    • First clinical stroke most frequently occurs between 2 and 8 years of age
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17
Q

What are other potential complications of SCD?

A
  • Aplastic crisis
  • Infections
  • Liver damage (multifactorial)
  • Splenic sequestration crisis
  • Megaloblastic anemia
  • Growth retardation
  • Bony abnormalities
  • Renal dysfunction
  • Leg ulcers
  • Cholelithiasis
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18
Q

What causes auto-spleenectomy in sickle cell patients?

A
  • Repeated episodes of splenic infarction, resulting in shrunken, fibrotic, non-functional spleen
  • Seen in essentially all adults with SS disease
  • Increased risk for infection by encapsulated bacteria
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19
Q

What is acute chest syndrome?

A
  • Severe complication, major cause of death
  • Result from pulmonary infections or fat emboli from infarcted marrow
  • Sluggish blood flow from inflammation causes sickling and vaso-occlusion, triggering vicious cycle
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20
Q
  • What causes aplastic crisis in sickle cell patients?
  • Why is this particularly dangerous for sickle cell patients?
A
  • Caused by acute decrease in RBC production
  • Usually due to parvovirus B19 infection
    • Common childhood virus (“Fifth’s disease”)
    • Infects erythroid precursors and cause red cell aplasia with absent erythropoiesis for 7-10 days
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21
Q

What is splenic sequestration crisis?

A
  • Acute pooling of blood in spleen
  • Precipitous drop in hemoglobin
  • Potential for hypovolemic shock
22
Q

What causes megaloblastic anemia?

A

Folate consumption because of chronic erythroid hyperproliferation

23
Q

Sickle Cell Disease

Laboratory Findings

A
  • Chronic anemia
    • ​steady state hemoglobin from 5-11 g/dl
      • most commonly about 7
  • Increased bilirubin
  • Sickled cells, target cells, and polychromasia
  • Increased reticulocytes
  • Normal MCV
  • Post-splenectomy changes in adults
24
Q

What do you expect to see on HPLC for a sickle cell disease patient?

A
25
Q

Describe Hemoglobin SC disease:

A
  • Compound heterozygous state
  • Hemoglobin C results from glu to lys substitution at the 6th amino acid of the beta globin chain
    • Does not apparently co-polymerize with HbS, but causes cellular dehydration and consequent sicking
  • Generally milder disease than SS, but highly variable
  • Hb levels usually 10 to 12 g/dl
26
Q

Describe Hb S/Beta thalassemia:

A
  • Heterozygous Hb S with trans beta thalassemia allele
    • resulting in decreased or absent production of normal beta chains
  • Ranges from asymptomatic to a disorder nearly identical to SS disease, depending on output of normal beta chains from thalassemia allele
  • Lab findings:
    • Hb S > Hb A
27
Q

How is sickle cell disease managed?

A
  • Newborn screening
  • Infection prophylaxis
  • Supportive care for acute manifestations
  • Hydroxyurea (most commonly used Tx for chronic disease management)
  • Regular red cell transfusions
  • Allogeneic stem cell transplant
28
Q

What is the benefit of using hydroxyurea for sickle cell patients?

A
  • Chemotherapy agent used to reduce blood cell counts in myeloproliferative neoplasms
  • Inhibits ribonucleotide reductase and causes cell cycle arrest
  • Increases erythrocyte levels of HbF, ameliorating the sickling manifestations
  • Dramatically reduces frequency of pain crises, as well as significantly decreased transfusion requirements, hospital admissions, incidence of acute chest sydrome
29
Q

What is the only cure for SCD?

A

Allogeneic stem cell transplant

30
Q

What is the prognosis/outcome for SCD?

A
  • Median age of death of 42 for males and 48 for females with SS disease
  • Gains mainly seen due to decreased mortality rates in children due to aggressive infection prophlaxis and comprehensive care approaches
  • No apparent decrease in mortality rates in adults over last several decades
31
Q

What are the major causes of death in sickle cell patients?

A
  • Liver dysfunction
  • Pulmonary hypertension
  • Stroke
  • Vaso-occlusive crisis
  • Acute chest syndrome
32
Q

S-Trait

  • How does it compare to sickle cell disease?
  • What is the major complication?
  • What are the Hb lab findings?
A
  • 8% of African Americans
  • Clinically benign
    • No anemia
    • Normal RBC survival
    • No crises or other complications in vast majority of patients
    • Normal peripheral blood smear
  • May be mild, sub-clinical kidney damage
    • Impairment of urine concentration
    • Microhematuria
  • Laboratory
    • 60% Hb A, 40% HbS
33
Q

What do you expect to see on HPLC for a sickle cell trait patient?

A
34
Q

What are the manifestations of HbC disease?

A
  • Mild to moderate hemolytic anemia
  • Often asymptomatic
  • Splenomegaly
    • May cause occasional abdominal pain
  • 1/6000 African Americans
35
Q
  • What is the pathophysiology of HbC disease?
  • How does it differ from SCD?
A
  • Glu to Lys substitution of amino acid 6 of β chain (β6Lys)
  • Cells abnormally rigid and dehydrated
  • RBC life span shortened to 30-35 days
  • Not a sickling disorder
36
Q

What are the expected CBC and Hb findings for HbC disease?

A
  • Hemoglobin levels range from 8-12 g/dl
  • >90% HbC
  • No HbA
37
Q

What can be seen on peripheral blood smear in a patient with HbC disease?

A
  • Numerous target cells
  • Mild microcytosis
  • Spherocytes
  • Occasional C crystals
38
Q

What are the manifestations of HbC trait?

A
  • 2% of African-Americans
  • No anemia
  • Few target cells
  • 50-60% HbA, 30-40% HbC
39
Q
  • Define thalassemias:
  • Distribution of β-thal and α-thal:
A
  • Group of inherited disorders characterized by decreased production of structurally normal globin chains
  • Highly heterogeneous both clinically and genetically
  • Distribution
    • β-thal: Mediterranean, Middle East, parts of India and Pakistan, and Southeast Asia
    • α-thal: Africa, Mediterranean, Middle East, and Southeast Asia
40
Q
  • What is the typical RBC morphology for thalassemia?
  • What determines the severity of hematologic manifestations?
A
  • Typically are microcytic, hypochromic anemias of varying severity
    • Decreased hemoglobin production produces hypochromia and microcytosis
      • “Cytoplasmic maturation defect”
  • Severity of hematologic manifestations is directly related to the degree of chain imbalance
    • Excess normally produced globin chains accumulate and cause intramedullary cell death and/or decreased RBC survival
41
Q
  • What is β thalassemia?
  • What mutations can cause it?
A
  • Decreased beta globin chain production from affected alleles
  • More than 250 mutations described:
    • Mutations causing splicing errors (most common)
    • Mutations in promoters causing decreased transcription
    • Translation errors (frameshift or nonsense codons)
    • Gene deletion rare
42
Q

How are β thalassemias classified?

A

Classified clinically because of extreme genetic heterogeneity

  1. β-thal major (Cooley’s anemia)
  2. β-thal intermedia
  3. β-thal minor
43
Q

Define β-thal major:

A
  • Absence or marked decrease in beta-chain production on both beta alleles
    • Excess of normal alpha chains, which are unable to form tetramers, and precipitate in normoblasts and erythrocytes
    • Intramedullary cell death and decreased RBC lifespan
      • Hybrid of hemolytic anemia and ineffective erythropoiesis
44
Q

What is the clinical progression of β-thal major?

A
  • Infants well at birth–anemia develops over the first few months of life
  • Severe anemia-baseline Hb of 2-3 g/dL
    • Virtually all Hb F
    • Bizarre red cell morphology (hypochromia, targeting, erythroblastosis)
  • Transfusion dependence
  • Severity of clinical effects depends on:
    • adequacy of transfusion program
    • efficacy of iron chelation
45
Q

Consequences of Inadequately Transfused β-Thal Major:

A
  • Stunted growth
  • Frontal bossing
  • “Mongoloid” facies
  • Increased skin pigmentation
  • Death in childhood
  • Characteristic bony abnormalities
  • Folate deficiency
  • Fever
  • Wasting
  • Hyperuricemia
  • Spontaneous fractures
  • Hepatosplenomegaly
  • Infections
46
Q

Consequences of Adequately Transfused β-Thal Major:

  • Without adequate iron chelation therapy
  • With adequate iron chelation therapy
A
  • Essentially normal early development
  • Avoidance of classic complications
  • Without adequate iron chelation therapy
    • Absence of pubertal growth spurt and menarche
    • Endocrine disturbances such as DM, adrenal insufficiency
    • Death from cardiac disease by end of third decade
  • With aggressive iron chelation therapy
    • Less severe cardiac disease and endocrine disturbances
    • Significantly improved life-span
47
Q

Define β-Thal Minor:

A
  • Heterozygous form
  • Asymptomatic
  • Discovered incidentally
  • Incidence
    • Common in Mediterranean and Asian populations
    • 1.5% of African Americans
48
Q

What are the lab findings for β-Thal Minor?

A
  • Mild or no anemia (Hb>~10g)
  • Microcytosis (50-70 fl)
  • Mild anisopoikilocytosis
    • Scattered target cells
  • Basophilic stippling
  • Elevated HbA2: 3.5-7%
49
Q

What is β-Thal Intermedia?

A
  • Heterogeneous group
  • Intermediate severity between beta thalassemia major and minor
50
Q

What causes α Thalassemia?

A

Usually a result of gene deletion

  • in contrast to the beta-thalassemias
51
Q

α-Thalassemia Clinical Subtypes:

  1. 1 α gene deleted:
  2. 2 α genes deleted:
  3. 3 α genes deleted:
  4. 4 α genes deleted:
A
  1. Silent carrier (1 alpha gene deleted)
  2. Alpha-thal trait (2 genes deleted)
    • Mild microcytic anemia similar to beta-thal minor, discovered incidentally
  3. Hemoglobin H disease (3 genes deleted)
    • Mild to moderate, chronic hemolytic anemia
    • Hb H represents beta tetramers
      • Does not effectively transfer oxygen
    • Hb H soluble, so does not initially precipitate in normoblasts (no intramedullary cell death)
      • Unstable over time, so precipitates in circulating red cells, causing hemolysis
  4. Hydrops fetalis (4 genes deleted)
    • Infants either stillborn or die within first few hours of life

Heme/Lymph (18 decks)

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