Heme/Lymph > Hemoglobinopathy > Flashcards

Hemoglobinopathy Flashcards

(51 cards)

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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?

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

What causes megaloblastic anemia?

Study These Flashcards
A

Folate consumption because of chronic erythroid hyperproliferation

23
Q

Sickle Cell Disease

Laboratory Findings

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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?

25
Describe **Hemoglobin SC** disease:
* 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
Describe **Hb S/Beta thalassemia:**
* **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
How is sickle cell disease managed?
* **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
What is the benefit of using **hydroxyurea** for sickle cell patients?
* 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
What is the only cure for SCD?
**Allogeneic stem cell transplant**
30
What is the prognosis/outcome for SCD?
* 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
What are the major causes of death in sickle cell patients?
* Liver dysfunction * Pulmonary hypertension * Stroke * Vaso-occlusive crisis * Acute chest syndrome
32
**S-Trait** * How does it compare to sickle cell disease? * What is the major complication? * What are the Hb lab findings?
* 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
What do you expect to see on **HPLC for a sickle cell trait patient**?
34
What are the manifestations of **HbC disease**?
* **Mild to moderate hemolytic anemia** * **Often asymptomatic** * **Splenomegaly** * May cause occasional abdominal pain * 1/6000 African Americans
35
* What is the pathophysiology of HbC disease? * How does it differ from SCD?
* **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
What are the expected CBC and Hb findings for HbC disease?
* **Hemoglobin levels range from 8-12 g/dl** * **\>90% HbC** * **_No HbA_**
37
What can be seen on peripheral blood smear in a patient with HbC disease?
* **Numerous target cells** * Mild microcytosis * **Spherocytes** * Occasional **C crystals**
38
What are the manifestations of **HbC trait**?
* 2% of African-Americans * **No anemia** * Few target cells * **50-60% HbA, 30-40% HbC**
39
* Define thalassemias: * Distribution of β-thal and α-thal:
* 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
* What is the typical **RBC morphology for thalassemia**? * What determines the **severity of hematologic manifestations**?
* 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
* What is β thalassemia? * What mutations can cause it?
* 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
How are β thalassemias classified?
Classified clinically because of **extreme genetic heterogeneity** 1. β-thal major (Cooley’s anemia) 2. β-thal intermedia 3. β-thal minor
43
**Define β-thal major:**
* **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
What is the **clinical progression of β-thal major**?
* **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
Consequences of **Inadequately Transfused β-Thal Major:**
* **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
Consequences of **Adequately Transfused β-Thal Major:** * **Without adequate iron chelation therapy** * **With adequate iron chelation therapy**
* 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
Define β-Thal Minor:
* **Heterozygous form** * **Asymptomatic** * Discovered incidentally * Incidence * Common in Mediterranean and Asian populations * 1.5% of African Americans
48
What are the **lab findings for β-Thal Minor**?
* Mild or no anemia (Hb\>~10g) * _Microcytosis_ (50-70 fl) * Mild anisopoikilocytosis * Scattered target cells * _Basophilic stippling_ * **Elevated HbA2:** 3.5-7%
49
What is β-Thal Intermedia?
* Heterogeneous group * Intermediate severity between beta thalassemia major and minor
50
**What causes α Thalassemia?**
Usually a result of **gene deletion** * in contrast to the beta-thalassemias
51
**α-Thalassemia Clinical Subtypes:** 1. 1 α gene deleted: 2. 2 α genes deleted: 3. 3 α genes deleted: 4. 4 α genes deleted:
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
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