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Heme 2 > Disorders of Hemoglobbin > Flashcards

Disorders of Hemoglobbin Flashcards

1
Q

Hemoglobin Disorders
• Structural variants
– Abnormal globin chain structure due to :
– Varied clinical effects depending on :

A

globin gene mutation

location and
nature of mutation in globin chains

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2
Q

– Under-production of structurally normal globin chains
– Generally microcytic/hypochromic anemias of
varying severity

A

Thalassemias

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3
Q

alpha globins located on chromosome ___

beta globins located on chromosome___

A

16 ( 2 sets thus 4 alleles)

11 (1 set, 2 alleles)

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4
Q

Three normal hemogobin species in fetal and
postnatal life
– Hemolobin A:
– Hemoglobin F:
– Hemoglobin A2:

which dominates during fetal life?

What is composition 1 year after life?

A

– Hemolobin A: (alpha2beta2) 96% 1 year
– Hemoglobin F: (alpha2gamma2) 1%
– Hemoglobin A2: (alpha2delta2) 3%

HgF dominates during fetal life

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5
Q

More than 500 structural hemoglobin variants have
been described
– Most are ________ in globin molecules
(due to single base pair substitutions in globin genes)
– Any globin gene may be affected
– Occasional other types of mutations

***most are clinically SILENT

A

single amino acid replacements

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6
Q

Consequences of HgB structual abnormalities depends on:

A
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7
Q

Possible consequences to structual hemoglobin abnormalities

A

– Sickling
– Instability
– Altered oxygen affinity (increased or decreased)
– Increased susceptibility to oxidation to methemoglobin
– Under-production

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8
Q

What two common Lab test do we do for Dx of hemoglobin disorders?

A

Hemoglobin electrophoresis
– Gel
– Capillary
• High performance liquid chromatography
(HPLC)

~isloelectric focusing/Globin chain electrophorysis/ gene mutation analysis as well

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9
Q

You decide to run Electorphoresis on pt suspected of HgB abnormality,

how is this typically performed?

What is HbA’s isoelectric point?

A

• Typically performed in parallel with alkaline and acid
buffers
• HbA has isoelectric point of 6.8

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10
Q

How electrophoresis works:

– Negative charge in alkaline buffers–migrates toward :
– Positive charge in acid buffers–migrates toward :

A

Anode (+)

Cathode (-)

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11
Q

In electrophoresis, migration of hemoblobin depends on what 2 factors?

A

– Net charge in alkaline electrophoresis
– Net charge and interaction with components of media in
acid electrophoresis

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12
Q

How does HPLC work in a whole blood method (whole blood hemosylate)

A

– 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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13
Q

Sickle Cell Disease
• Homozygous abnormality of the ____ globin chain
• ___to____substitution at amino acid 6
• Heterozygous HbS (S-trait) confers protection
against_____

A

beta

Glu to Val

malaria

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14
Q

How common is Hb S gene?

A

– 4% allelic frequency for Hb S gene among AfricanAmericans
– Rare in other ethnic groups
• Homozygous S occurs at a frequency of 1 in 600
in African Americans

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15
Q

Describe pathophysiology of SS anemia

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

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16
Q

What does Hb S polymerization depend on?

A

• Extent of HbS polymerization is time and
concentration dependent

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17
Q

Factors that affect concentration of HbS

A

• Percentage of hemoglobin S of total hemoglobin (homo vs heteroZ or if there are other Hb species~ like HbF
• Total hemoglobin concentration in the red cells (MCHC)
– Increased in cellular dehydration
– Decreased if co-existent thalassemia

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18
Q

Time Dependence of Sickling
• Importance of transit time of red cells through ________ microvasculature

A

low oxygen tension

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19
Q

Time Dependence of Sickling

Sickling enhanced in anatomic sites with _____ (e.g., spleen and bone marrow)
• Blood flow through microvasculature retarded in certain pathologic states like:

A

sluggish flow

– Inflammation

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20
Q

Clinical Settings Predisposing
to Sickling

A
  • Hypoxia
  • Acidosis
  • Dehydration
  • Cold temperatures
  • Infections (multiple mechanisms)
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21
Q

Why does acidosis predispose someone to sickling?

what about dehydration?

A

– Shift of oxygen dissociation curve to right, causing increased deoxygenation of Hb S

leads to hypertonicity leading to RBC dehydration

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22
Q

• SS cells begin to sickle at ~___mm Hg
• Sickling is initially a_____ process, but
after multiple sickling/unsickling cycles,
membrane damage produces an irreversibly sickled cell
• RBC lifespan decreased to___ days

A

40mm Hg

reversible

20

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23
Q

2 bad Effects of RBC Sickling

A

• Chronic hemolysis

• Microvascular occlusion with resultant tissue
hypoxia and infarction

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24
Q

– Correlates with the number of irreversibly sickled cells

A

Chronic hemolysis in SS anemia

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25
Q

Related to increased “stickiness” of SS red cells
because of membrane damage

A

• Microvascular occlusion with resultant tissue
hypoxia and infarction

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26
Q

SS anemia:

  • Newborns clinically fine because of ____
  • Hematologic manifestations begin by ____ weeks of age
  • Clinical severity____ from patient to patient
A

high HbF levels

10-12

variable

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27
Q

Clinical manifestations of SS anemia

A

Severe anemia

Acte pain crisis from vaso-occusion

Auto-spenectomy~~ shrunken spleeen, no functional

Acute Chest Syndrome~ major cause of deaht

Stokes

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28
Q

Auto-splenectomy in SS anemia:
– Repeated episodes of _______, resulting in shrunken, fibrotic, nonfunctional spleen
– Seen in essentially all adults with SS disease
– Increased risk for infection by ______

A

splenic infarction

encapsulated bacteria

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29
Q

– Severe complication, major cause of death in SS anemia
– Result from pulmonary infections or fat emboli from infarcted marrow
– Sluggish blood flow from inflammation causes sickling and vaso-occlusion,
triggering vicious cycle

A

Acute chest syndrome

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30
Q

Strokes in SS anemia
– Risk of stroke of 11% by age___
– First clinical stroke most frequently occurs between ___ and ___years of age

A

20

2 and 8

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31
Q

Aplastic crisis seen in SS anemia:
– Caused by acute decrease in ____
– Usually due to _____infection

A

RBC production

parvovirus B19 : Infects erythroid precursors and cause red cell aplasia with absent erythropoiesis for 7-10 days

32
Q
A
33
Q

– Acute pooling of blood in spleen
– Precipitous drop in hemoglobin
– Potential for hypovolemic shock

A

• Splenic sequestration crisis seen in SS anemia

34
Q

Megaloblastic anemia in SS anemia caused by
Folate consumption because of

A

chronic erythroid hyperproliferation

35
Q

More clincal manifestations of SS anemia

A
  • Growth retardation
  • Bony abnormalities
  • Renal dysfunction
  • Leg ulcers
  • Cholelithiasis
36
Q

SS anemia Lab Findings:

____ bilirubin

____MCV

_____reticulocytes

A

SS anemia:

Increased bilirubin

Normal MCV

increased reticulocytes

37
Q

Describe what you would see on a PB smear in pt with SS anemia

A

Sickled cells

Target cells

polychromasia

38
Q

Pt with chronic SS anemia will have what kind of HgB?

A

steady state from 5-11 (most common around 7)

39
Q

• Hemoglobin SC disease
– Compound_____ state
– Hemoglobin C results from _____substitution at the 6th amino acid
of the beta globin chain

A

heterozygous

glu to lys

40
Q

which is worse; Hb SC or Hb SS?

What are HgB levels like in both diseases?

A

Hb SC is milder with HgB = 10-12

SS anemia ~ 7

41
Q

Hb S/Beta thalassemia
– Heterozygous Hb S with trans beta thalassemia allele, resulting in:

A

decreased or absent production of normal beta chains

42
Q

Describe symptomatology and labs seen in HbS/Beta thalassemia

A

– 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

43
Q

How do we manage pts with SS anemia?

A
  • Newborn screening
  • Infection prophylaxis
  • Supportive care for acute manifestations
  • Hydroxyurea
  • Regular red cell transfusions
  • Allogeneic stem cell transplant
44
Q

Hydroxyurea
– Chemotherapy agent used to ______in myeloproliferative neoplasms
– Inhibits _____ and causes cell cycle arrest
– Increases erythrocyte levels of____, ameliorating the sickling manifestations

A

reduce blood cell counts

ribonucleotide reductase

HbF

45
Q

Benefits of hydroxyurea for pts with SS anemia

A

– Dramatically reduces frequency of pain crises, as well as significantly
decreased transfusion requirements, hospital admissions, incidence of acute
chest sydrome

46
Q

SS anemia outcomes

Median age of death of___ for males and___ 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

A

42, 48

47
Q

Major causes of death in adults with SS anemia

A

• Major causes of death in adults:
– Liver dysfunction
– Pulmonary hypertension
– Stroke
– Vaso-occlusive crisis
– Acute chest syndrome

48
Q

S-trait seen in ___% of AA and has what clinical significance?

A

S-Trait
• 8% of African Americans
• Clinically benign

May be mild, sub-clinical kidney damage~ impaired urine conc or microhematuria

49
Q

What do we see on Labs in pt w/ S trait?

A

– 60% Hb A, 40% HbS

50
Q

Mild to moderate hemolytic anemia
• Often asymptomatic
• Splenomegaly
– May cause occasional abdominal pain
• 1/6000 African Americans

A

HbC disease or CC

51
Q

HbC pathophysiology:

  • __ to ___ substitution of amino acid 6 of Beta chain
  • Cells abnormally______

• RBC life span shortened to ____ days
• Not a sickling disorder

A

Glu to Lys

rigid and dehydrated

30-35

52
Q

HbC Disease-Lab Findings

~ what kind of cells on PBS

~ HgB levels

A
  • Hemoglobin levels range from 8-12 g/dl
  • Numerous target cells
  • Mild microcytosis
  • Spherocytes
  • Occasional C crystals
53
Q

In HbC, what is the % composition for:

  • HbC
  • HbA
  • HbF
A
  • >90% HbC
  • No HbA
  • <7% HbF
54
Q
  • 2% of African-Americans
  • No anemia
  • Few target cells
  • 50-60% HbA, 30-40% HbC
A

HbC Trait

55
Q

Group of inherited disorders characterized by
decreased production of structurally normal globin chains

Highly heterogeneous both clinically and genetically

A

Thalassemias

56
Q

Thalessemia seen in: Wide distribution in Mediterranean, Middle
East, parts of India and Pakistan, and Southeast Asia

A

Beta-Thal

57
Q

Thalessemia Occurs throughout Africa, Mediterranean,
Middle East, and Southeast Asia

A

Alpha-thal

58
Q

Thalessemias are usually:

Macrocytic or microcytic

normochromic or hypochromic

A

Decreased hemoglobin production produces
hypochromia and microcytosis

– “Cytoplasmic maturation defect”

59
Q

In Thalessemias: Severity of hematologic manifestations is directly
related to _________

A

the degree of chain imbalance

– Excess normally produced globin chains accumulate
and cause intramedullary cell death and/or decreased RBC survival

60
Q

Beta Thalessemia:

• Decreased beta globin chain production from affected alleles:

is this more due to deletion or mutation?

A

MOre mutation, rarely deletion

most often dt splicing errors

61
Q

– Beta-thal major (Cooley’s anemia)
– Beta-thal intermedia
– Beta-thal minor

How are these classified?

A

Classified clinically because of extreme genetic
heterogeneity

62
Q

Absence or marked decrease in beta-chain production on both beta
alleles

A

Beta-Thal Major

63
Q

In Beta Thal Major:

– Excess of _____chains, which are unable to form tetramers,
and precipitate in normoblasts and erythrocytes
– Intramedullary cell death and decreased RBC lifespan

A

normal alpha

64
Q

How do infants with Beta-Thal Major do?

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 dependent

65
Q

In Beta-Thal Major: Severity of clinical effects depends on what two things?

A

adequacy of transfusion program and efficacy of iron chelation

66
Q

Inadequately transufsed Beta-Thal Major laundry list of issues:

A

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

67
Q

Adequately Transfused B-Thal Major experience
• Essentially normal early development
• Avoidance of classic complications but also require:

A

Iron chelation therapy

68
Q

What outcomes do we expect in pt receive adequate transfusions but without iron chelaiton with Beta-Thal Major?

A

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

69
Q

With aggressive iron chelation therapy how do our outcomes change?

A

– Less severe cardiac disease and endocrine disturbances
– Significantly improved life-span

70
Q

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

A

Beta-Thal Minor

71
Q

Labs in Beta-Thal Minor:

HgB:

Micro/macro/normocytosis

PBS

most important Diagnostic in labP

A

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

72
Q

if we see HbA2 elevated to 3.5-7 % what is this indicitive of?

A

Beta-Thal Minor

73
Q

Alpha Thalassemias usually a result of:

A

gene DELETION

74
Q

Alpha Thalassemias:

Silent carrier =

Alpha-Thal trait =

A

1 gene deleted

2 gene deleted w/ mild microcytic anemia simular to Beta-Thal minor

75
Q

What happens when we have 3 alpha genes deleted?

A

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

76
Q

What is hydrops fetalis?

A 
Hydrops fetalis (4 alpha genes deleted)
• Infants either stillborn or die within first few hours of life

Heme 2 (14 decks)

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