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WILLIAM'S HEMATOLOGY > 50 Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities > Flashcards

50 Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities Flashcards

1
Q

The iron-containing oxygen-transport metalloprotein found in abundance in the red blood cells.

A

Hemoglobin (Hb)

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2
Q

Accounts for about 2% of the Hb of normal adults

A

Minor adult Hb (HbA2 [α2δ2])

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3
Q

The prosthetic group of Hb

A

Heme (ferroprotoporphyrin IX)

The heme group is located in a crevice between the E and F helices in each globin chain

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4
Q

The non–α (β, γ, δ, or ε)-globin chains are all _____amino acids in length.

A

146 amino acids

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5
Q

P50 is standardized at ___°C and pH ____°C.

A

37°C

pH 7.20

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6
Q

The point at which the Hb is one-half saturated with oxygen and is the usual measurement of oxygen affinity

A

P50

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7
Q

TRUE OR FALSE

The vast majority of Hb variants arose as a result of single nucleotide mutations, leading to an amino acid change in either α-globin, β-globin, δ-globin, or γ-globin subunits of the Hb tetramer.

A

TRUE

The vast majority of Hb variants arose as a result of single nucleotide mutations, leading to an amino acid change in either α-globin, β-globin, δ-globin, or γ-globin subunits of the Hb tetramer.

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8
Q

HbE prevalence is second only to HbS, and found principally in Burma, Thailand, Laos, Cambodia, Malaysia, and Indonesia, but not in ______

A

China

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9
Q

Single nucleotide mutations in:

HbS:
HbD:
HbC:
HbE:

A

HbS: B6Glu–>Val
HbD:B121Glu–>Gln
HbC: B6Glu–>Lys
HbE: B26Glu–>Lys

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10
Q

The World Health Organization estimates that ____% of the world population carries a gene for a hemoglobinopathy.

A

5%

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11
Q

Aggregation of deoxy HbS molecules into polymers occurs when aggregates reach a thermodynamically critical size

A

Homogenous nucleation

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12
Q

The smallest aggregate formed that favors polymer growth

A

Critical nucleus

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13
Q

Addition of subsequent deoxy HbS molecules to already formed polymers

A

Heterogenous nucleation

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14
Q

A key signaling molecule of the vascular endothelium, has vasodilatory, antiinflammatory, and antiplatelet properties

A

Nitric oxide (NO)

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15
Q

Released as a consequence of sickle red cell hemolysis converts arginine to ornithine, thereby limiting l-arginine availability for NO synthesis.

A

L-arginase

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16
Q

The site of adhesion of sickle red cells is purported to be the __________

A

Postcapillary venule

The site of adhesion is purported to be the postcapillary venule at which site sickle red cells appear to interact with white cells adherent to the endothelium rather than engaging the endothelium directly

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17
Q

TRUE OR FALSE

Neutropenia is an adverse prognostic factor in sickle cell anemia.

A

FALSE

Neutrophilia is an adverse prognostic factor in sickle cell anemia.

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18
Q

A potent vasoconstrictor and upregulation is associated with adverse outcomes in SCD

A

Endothelin-1

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19
Q

Characteristics of the vascular beds in sickle cell anemia

A

Large vessel intimal hyperplasia and smooth muscle proliferation

Lipid-laden plaques of atherosclerotic vascular disease are not present

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20
Q

The major component of microparticles in SCD

A

Erythrocyte and platelet microparticles (TF-NEGATIVE)

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21
Q

The major contributor of microparticle-dependent coagulation activation in SCD

A

Activation of the intrinsic pathway of coagulation by TF-negative, red cell, and platelet microparticles through a phosphatidylserine-dependent mechanism

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22
Q

Adenosine Signaling

Adenosine A2A receptor:
Adenosine A2B receptor:

A

Adenosine A2A receptor: expressed on most leukocytes and platelets results in an antiinflammatory effect

Adenosine A2B receptor: causes priapism in SCD mice via hypoxia inducible factor-1–mediated decrease of phosphodieasterase; leads to increased 2,3-BPG in red cells causing decreased oxygen binding affinity of Hb, which promotes sickling

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23
Q

Inheritance of only 1 HbS allele along with a normal β-globin gene is termed

A

Sickle cell trait (HbAS)

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24
Q

HbAS cells sickle at O2 tension of approximately _______ torr

A

15 torr

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25
Q

The most common manifestations of HbAS/sickle cell trait

A

Renal abnormalities

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26
Q

A rare but serious renal complication of HbAS

A

Renal medullary carcinoma

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27
Q

TRUE OR FALSE

HbAS patients do not have increased perioperative morbidity or mortality.

A

TRUE

HbAS patients do not have increased perioperative morbidity or mortality.

The life span of HbAS individuals is normal.

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28
Q

Lab parameter that is reflective of persistent low-grade inflammation in SCD

A

Elevated neutrophil and platelet levels

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29
Q

Correlate with SCD complications and disease severity

A

High viscosity and high percentage of dense red cells

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30
Q

Dense cells, defined as having more than ____g/L of Hb, are more likely to sickle

A

111 g/L of Hb

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31
Q

Blood viscosity is determined by the:

A

Hematocrit, red blood cell deformability, red cell aggregation, and plasma viscosity.

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32
Q

A ______hematocrit-to-viscosity ratio indicates improved oxygen-carrying capacity, and it is _____in patients with SCD compared to normal individuals

A

Higher hematocrit-to-viscosity ratio

Lower in patients with SCD

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33
Q

The clinical hallmark of SCD

A

Vasoocclusive Crisis

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34
Q

Pain becomes severest by day ____

A

3

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35
Q

VOC become more frequent during

A

Transition from teenage years to young adulthood

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36
Q

Most common precipitating factor of VOC

A

In most cases no precipitating factor is found.

Episodes may be precipitated by insomnia, emotional stress, dehydration, infection, and cold weather

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37
Q

Results when there is a marked reduction in red cell production in the face of ongoing hemolysis, causing an acute, severe drop in Hb level

A

Aplastic crisis

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38
Q

The characteristic laboratory finding in aplastic crisis

A

Reticulocyte count less than 1%

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39
Q

The most common cause of Aplastic crisis in SCD

A

Parvovirus B19 infection

Attaches to the P-antigen receptor on erythroid progenitor cells

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40
Q

In aplastic crisis, patients usually recover within

A

2 weeks

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41
Q

Cause severe, life-threatening anemia due to sudden, massive pooling of red cells, typically in the spleen, and less commonly, the liver

A

Sequestration Crisis

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42
Q

Splenic sequestration is typically seen in

A

Children younger than 5 years prior to autoinfarction of the spleen

Also can be seen in adolescents or adults with HbSC disease or HbSβ-thalassemia with persisting splenomegaly

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43
Q

Treatment for Splenic sequestration

A

Small, cautious red cell transfusion

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44
Q

TRUE OR FALSE

Emergency splenectomy during a sequestration crisis is recommended.

A

FALSE

Emergency splenectomy during a sequestration crisis is not recommended.

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45
Q

Chronic red cell transfusion may be used as a means of delaying splenectomy until the child is ______ years or older, at which time splenectomy may be considered.

A

2 years or older

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46
Q

The occurrence of episodes of accelerated rates of hemolysis characterized by decreased Hb concentration and increased levels of reticulocytes and other markers of hemolysis (hyperbilirubinemia, increased LDH)

A

Hyperhemolytic Crisis

***can occur during resolution of a VOC and from an acute or delayed hemolytic transfusion reactions

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47
Q

Acute pain is managed with ___________________ or a combination of these medications.

A

Opioids, nonsteroidal antiinflammatory drugs, acetaminophen

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48
Q

Occasionally, severe, unrelenting pain may require red cell transfusion to decrease HbS below _________.

A

30%.

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49
Q

Constellation of signs and symptoms in patients with SCD that includes a new infiltrate on chest radiograph defined by alveolar consolidation, but not atelectasis, that may be accompanied by chest pain, fever, tachypnea, wheezing, cough and/or hypoxia

A

Acute chest syndrome (ACS)

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50
Q

A leading cause of mortality in patients with SCD

A

Acute chest syndrome (ACS)

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51
Q

Etiology of ACS varies depending on age:

Pediatric age group:
Adults:

A

Etiology of ACS varies depending on age:

Pediatric age group: viral and bacterial infections
Adults: fat embolization resulting from marrow necrosis

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52
Q

Important pathogens for ACS

A

Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Parvovirus B19, respiratory syncytial virus, and influenza

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53
Q

Pathogenesis of ACS

A

Increased intrapulmonary sickling, intrapulmonary inflammation with increased microvascular permeability, and alveolar consolidation

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54
Q

Independent risk factors for respiratory failure in ACS

A

Age older than 20 years
Platelet count less than 20 × 109/L
Multilobar lung involvement,
A history of cardiac disease

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55
Q

An independent predictor of neurologic complications during hospitalization for ACS

A

Thrombocytopenia

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56
Q

Management of ACS

A

Incentive spirometry, adequate pain control to avoid chest splinting, antimicrobial therapy

Avoidance of overhydration, use of bronchodilators, and red cell transfusion to decrease intrapulmonary sickling

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57
Q

Exchange transfusion in ACS is ideal, but simple transfusions to a target Hb of ____g/L are most often used for expediency.

A

100g/L

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58
Q

Should be offered to all patients with a history of ACS because it reduces the incidence by 50% in children and 73% in adults.

A

Hydroxyurea

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59
Q

Patients with SCD should be screened for PH by________________ at steady-state.

A

Echocardiogram

60
Q

Referral to a pulmonary specialist for further evaluation of PH should be done among the following:

A

A tricuspid regurgitation velocity of 2.5 m/sec + brain natriuretic peptide is greater than 160 pg/mL

Tricuspid regurgitation velocity is faster than 2.9 m/s regardless of the brain natriuretic peptide

61
Q

May be a good modality to image microvascular flow and quantitate cardiac iron overload

A

Cardiac magnetic resonance

62
Q

Risk of stroke is highest in the _____decade of life followed by a second smaller peak after age 29 years.

A

First decade of life

63
Q

Types of strokes in SCD:

Ischemic stroke :
hemorrhagic stroke:

A

Ischemic stroke :children and older adults
hemorrhagic stroke:third decade of life

64
Q

Recurrent stroke is most common in the first ____years following the primary event

A

2 years following the primary event

65
Q

Risk factors for stroke in SCD

A

Ischemic:transient ischemic attack, recent or recurrent ACS, nocturnal hypoxemia, silent infarcts, hypertension, elevated LDH, and leukocytosis

Hemorrhagic: anemia, neutrophilia, the use of glucocorticoids, and recent transfusion

66
Q

The best predictor of stroke risk in SCD

A

Increased blood flow velocity in major intracranial arteries on TCD ultrasonography

67
Q

Velocities between 170 and 200 cm/s are termed_____________

A

Conditional

68
Q

Velocities faster than _____cm/s are considered high and are associated with a 10-fold increase in ischemic stroke in children 2–16 years of age

A

200 cm/s

69
Q

Associated with increased large-vessel stroke risk

A

TNF (−308) G/A promoter polymorphism

70
Q

Variant associated with protection against stroke

A

ENPP1 K173Q

71
Q

Based on the results from the Stroke Prevention in Sickle Cell Disease (STOP) Study, it is recommended that asymptomatic children with HbSS disease older than ______years should be screened for stroke risk using TCD.

A

Older than 2 years

*Those with high TCD velocities should be offered a chronic red cell transfusion program for primary stroke prevention.
**Repeat TCD screenings should be done every 3–12 months

72
Q

Prevention of Secondary Stroke: _______ may be preferable to periodic red cell transfusion not only to avoid iron overload, but also to further reduce stroke risk.

A

Exchange transfusion

73
Q

Once a serum creatinine equal to or greater than _____ mg/dL develops, time to death averages ____ years.

A

1.5 mg/dL

4 years

74
Q

The most common cause of acute renal failure in SCD.

A

Dehydration

75
Q

TRUE OR FALSE

Hyposthenuria, or difficulty concentrating urine, is highly prevalent in SCD, may increase the risk of dehydration, and is reversible

A

FALSE

Hyposthenuria, or difficulty concentrating urine, is highly prevalent in SCD, may increase the risk of dehydration, and is irreversible

76
Q

An accurate marker of glomerular filtration and is preferable to serum creatinine in estimating renal function

A

Cystatin C

77
Q

Priapism affects at least_____% of male patients with SCD

The mean age of onset is ____ years

A

35%

15 years

78
Q

Priapism episodes that last less than 3 hours

A

“stuttering priapism”

79
Q

The major contributors to priapism in SCD

A

Derangements in NO metabolism and adenosine signaling

80
Q

More than 95% of priapism is the ________type resulting from ischemia, is painful, and is a medical emergency

A

“low-flow” type

81
Q

Condition associated with priapism wherein transfusion therapy has resulted in neurologic sequelae

A

ASPEN syndrome (Association of Sickle Cell Disease, Priapism, Exchange Transfusion)

Thought to be secondary to hyperviscosity

Therefore, must be taken not to increase the hematocrit above 30%.

82
Q

In recalcitrant cases, a__________ is performed, but this results in permanent impotence

A

Shunt

83
Q

Typical serotypes of ____________________are the principal infectious offenders in osteomyelitis

A

Salmonella, S. aureus, and Gram-negative bacilli

84
Q

Culture results may be nondiagnostic because patients usually receive antibiotics on presentation with fever; therefore, the presence of __________________should evoke a high suspicion for osteomyelitis.

A

Leukocytes in bone and joint aspirates

85
Q

Osteopenia and osteoporosis are prevalent (30–80%) in patients with SCD, with a predilection for the _____________

A

Lumbar spine

86
Q

Vasoocclusion resulting in infarction of articular surfaces of long bone occurs, most commonly in the femur followed by the humerus

A

Avascular Necrosis

87
Q

Classic risk factors for AVN

A

Concurrent deletional α-thalassemia (−α3.7)
History of frequent VOCs

OTHERS:
Male gender, higher Hb concentration, low HbF, and vitamin D deficiency

88
Q

Polymorphisms in ___________________________ genes are associated with AVN.

A

BMP6, ANNEXIN A2 KLOTHO, IL1B, and S100B

89
Q

The incidence of leg ulcers varies geographically, with the highest rate reported in_____________

A

Jamaica

90
Q

Leg ulcers occur on the lower extremities, especially on the _______

A

Malleoli

91
Q

Protective against leg ulcers

A

Coinheritance of α-thalassemia

92
Q

Polymorphisms associated with leg ulcers

A

KL (encoding Klotho), TEK (encoding tyrosine kinase endothelial), and several other genes in the transforming growth factor-β and bone morphogenic protein pathways

93
Q

Characterized by a rapidly enlarging, tender liver and hypovolemia is akin to splenic sequestration but much more rare.

It requires prompt treatment with red cell transfusion.

A

Acute hepatic sequestration crisis

94
Q

Ophthalmic changes include “salmon-patch” hemorrhages, peripheral retinal lesions termed black sunbursts, and iridescent spots

A

Nonproliferative changes

95
Q

Ophthalmic changes include pattern of vascular lesions resembling a marine invertebrate that is termed sea fans

A

Proliferative changes

96
Q

Characterized by fever, headache, orbital swelling, and visual impairment secondary to optic nerve dysfunction

A

Orbital compression syndrome

97
Q

Treatment for Central retinal artery occlusion

A

Urgent exchange transfusion

98
Q

Treatment for Orbital compression syndrome

A

Glucocorticoids with the addition of antibiotics

99
Q

Defined as impaired mononuclear phagocyte system functions in the spleen occurs in 86% of infants with SCD

Defined by the presence of Howell-Jolly bodies and absence of 99mtechnetium splenic uptake, even in the presence of a palpable spleen

A

Functional asplenia

100
Q

Repeated splenic infarctions lead to ______

A

“autosplenectomy”

101
Q

______________ may lead to reversal of functional asplenia.

A

Chronic transfusion prior to age 7 years

102
Q

Management During Anesthesia and Surgery
Transfusion to keep Hb levels at approximately ________is recommended

A

100 g/L

103
Q

________________ occurs in 30% to 50% of SCD patients and two-thirds of all deliveries will have infants with ____________________.

A

Preterm delivery

Birth weights less than the 50th percentile

104
Q

Management and Prevention of Infection: Oral penicillin prophylaxis

Between 0 and 3 years of age:
Between 3 and 5 years of age:

A

Management and Prevention of Infection: Oral penicillin prophylaxis

Between 0 and 3 years of age: 125 mg twice a day for children with HbSS or HbSβ0
Between 3 and 5 years of age: 250 mg twice a day

105
Q

Drug of choice for invasive pneumococcal disease

A

Ceftriaxone

106
Q

2 factors that ameliorate many complications of SCD

A

Inheritance of α-thalassemia trait
High fetal Hb

107
Q

TRUE OR FALSE

The γ-chains of HbF are excluded from the deoxy HbS polymer; thus the presence of HbF in sickle red cells exerts a potent antisickling effect.

A

TRUE

The γ-chains of HbF are excluded from the deoxy HbS polymer; thus the presence of HbF in sickle red cells exerts a potent antisickling effect.

108
Q

Hemoglobin F–Inducing Therapies: Mechanism

Stress erythropoiesis
Antiinflammatory
Nitric oxide donor
Increased cyclic guanosine monophosphate

A

Hydroxyurea

109
Q

Hemoglobin F–Inducing Therapies: Mechanism

DNA methyltransferase-1 inhibition, ie,mhypomethylation

A

Decitabine
5′-Azacitidine

110
Q

Hemoglobin F–Inducing Therapies: Mechanism

Histone deacetylase inhibition

A

Butyrate derivatives
Histone deacetylase inhibitors

111
Q

Hemoglobin F–Inducing Therapies: Mechanism

P38 mitogen-activated protein kinase pathway

A

Immunomodulatory drugs

112
Q

Hemoglobin F–Inducing Therapies: Mechanism

Reversal of γ-globin silencing

A

Pomalidomide

113
Q

Hemoglobin F–Inducing Therapies: Mechanism

Induction of FOXO3

A

Metformin

114
Q

It is a ribonucleotide reductase inhibitor and is S-phase specific in the cell cycle.

Its myelosuppressive effect leads to the recruitment of early erythroid progenitors that have retained their fetal (γ) globin synthesis capability, giving rise to the production of red cells with a higher HbF content.

A

Hydroxyurea

115
Q

Hydroxyurea is recommended in patients with

A

3 or more VOCs
History of ACS
2 years of age or older and have recurrent moderate to severe pain crises.

116
Q

Starting dose of HU

A

15 mg/kg given as a single daily dose and escalated by 5 mg/kg per day every 8 weeks until toxicity or a maximum dose of 35 mg/kg is reached.

117
Q

Maximum tolerated dose of HU is defined as

A

Dose that targets an absolute neutrophil count of 2.0–4.0 × 109/L and absolute reticulocyte count of 100–200 × 109/L

118
Q

Examples of histone deacetylase inhibitors

A

Butyrate derivatives (arginine butyrate, sodium phenylbutyrate, isobutyramide)

119
Q

DNA methyltransferase inhibitors

A

5-azacytidine and decitabine

120
Q

5-azacytidine or Decitabine

Incorporates only in DNA and is believed to have a better genotoxicity profile

A

Decitabine

Incorporates only in DNA and is believed to have a better genotoxicity profile

121
Q

The major factor in the switch from β-globin to γ-globin

A

KLF-1–BCL11A axis

122
Q

Most common indications for SCT in SCD

A

Cerebrovascular disease, recurrent ACS, and frequent VOCs despite adequate hydroxyurea therapy

*AHSCT should be done in patients who are likely to have a severe disease course, but should be instituted early, prior to end-organ damage.

123
Q

Indications for red cell transfusion in SCD

A

Symptomatic anemia, ACS, stroke, aplastic and sequestration crises, other major organ damage secondary to vasoocclusion, and occurrence of unrelenting priapism

124
Q

The best-established indication for chronic transfusion

A

Stroke and n abnormal TCD velocity if obtained while on hydroxyurea

To prevent stroke while hydroxyurea is being initiated

125
Q

Inappropriate indications for transfusion

A

Chronic steady-state anemia, uncomplicated VOC, minor surgical procedures, infection, and AVN

*Simple or exchange transfusion of red blood cells can be used.

126
Q

Has the advantage of not raising total Hb, and thereby blood viscosity, while decreasing the percentage of circulating sickle cells as sickle cell patients transport less oxygen to their tissues beyond a hematocrit of 30% as a result of increased blood viscosity.

A

Exchange transfusion

127
Q

Condition where Hb falls below pretransfusion levels and can be associated with a depressed reticulocyte count and autoantibodies

HbA may still be present, with the ratio of HbA:HbS expected posttransfusion preserved

A

Hyperhemolysis syndrome

128
Q

Treatments for hyperhemolysis

A

Steroids, intravenous immunoglobulins, and rituximab

129
Q

A better chelator of cardiac iron because of its ability to cross cell membranes

A

Deferiprone

130
Q

A small molecule that modifies HbS by binding to the α-globin subunit and stabilizing the R-state of Hb conformation, increasing Hb oxygen affinity and reducing polymerization,

A

Voxelotor (Oxbryta)

131
Q

A P-selectin monoclonal antibody that blocks interaction of P-selectins with leukocytes

A

Crizanlizumab

132
Q

Most of the Hb variants are ________________ mutations in the globin genes (α, β, γ, or δ) resulting from single nucleotide substitutions.

A

Missense mutations

133
Q

The precipitation of the unstable Hb molecule within the red cell with attachment to the inner layer of the red cell membrane

A

Heinz body” formation

134
Q

Red cells containing membrane-attached Heinz bodies have impaired deformability and filterability leading to their premature destruction

A

Congenital Heinz body hemolytic anemia

135
Q

Variant Hbs are usually found in the _____________ state

A

Heterozygous

136
Q

The second Hb variant described after HbS

A

HbC

137
Q

The second most common form of SCD in the United States, being found in approximately 25% of individuals with SCD

A

HbSC disease

138
Q

Fourth abnormal Hb described

A

Hemoglobon E disease

139
Q

Areas where Hgb E is prevalent

A

Southeast Asia; in some areas (in the border between Thailand, Laos, and Cambodia, the so-called HbE triangle)

140
Q

Third variant Hb identified

A

Hemoglobon D disease

141
Q

Result from mutations around the heme pocket that disrupt the hydrophobic nature of this structure with resultant oxidation of the iron in the heme moiety from ferrous (Fe2+) to ferric (Fe3+) state and cause methemoglobinemia

A

M Hbs

142
Q

Mutations that stabilize the molecule in the________________ state lead to low oxygen affinity variants, which can clinically manifest as cyanosis or mild anemia

A

T (tense, deoxy) state

143
Q

Mutations that stabilize the____________ state or destabilize the T state result in high O2 affinity variants. These variants will cause secondary erythrocytosis

A

R (relaxed, oxy) state

144
Q
A
145
Q
A

WILLIAM'S HEMATOLOGY (90 decks)

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