50 Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities Flashcards
(148 cards)
1
Q
The iron-containing oxygen-transport metalloprotein found in abundance in the red blood cells.
A
Hemoglobin (Hb)
2
Q
Accounts for about 2% of the Hb of normal adults
A
Minor adult Hb (HbA2 [α2δ2])
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
4
Q
The non–α (β, γ, δ, or ε)-globin chains are all _____amino acids in length.
A
146 amino acids
5
Q
P50 is standardized at ___°C and pH ____°C.
A
37°C
pH 7.20
6
Q
The point at which the Hb is one-half saturated with oxygen and is the usual measurement of oxygen affinity
A
P50
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.
Other mechanisms for producing Hb variants include small deletions or insertions, elongated chains, and fusions
8
Q
The most common SCD genotype is
in the US
A
Homozygous HbS (HbSS)
- Common SCD genotypes include HbSC, HbSβ+-thalassemia (HbSβ+), and HbSβ0-thalassemia (HbSβ0)
- Other less-common SCD genotypes include HbSDPunjab, HbSOArab, HbSLepore, and HbSE
9
Q
HbE prevalence is second only to HbS, and found principally in Burma, Thailand, Laos, Cambodia, Malaysia, and Indonesia, but not in ______
Asia
A
China
As with HbS and HbC, HbE appears to confer some resistance to infection with malaria.
10
Q
Single nucleotide mutations in:
HbS:
HbD:
HbC:
HbE:
A
HbS: B6Glu–>Val
HbD:B121Glu–>Gln
HbC: B6Glu–>Lys
HbE: B26Glu–>Lys
Sick si Val, Si Glyn hinD but Lys has LiCE (6-121-6-26)
11
Q
The World Health Organization estimates that ____% of the world population carries a gene for a hemoglobinopathy.
A
5%
12
Q
The sine qua non of sickle cell anemia is
A
Glu→Val substitution in the sixth amino acid of the β-globin molecule
13
Q
Aggregation of deoxy HbS molecules into polymers occurs when aggregates reach a thermodynamically critical size
A
Homogenous nucleation
14
Q
The smallest aggregate formed that favors polymer growth
A
Critical nucleus
15
Q
Addition of subsequent deoxy HbS molecules to already formed polymers
A
Heterogenous nucleation
- The quaternary structure of oxy HbS cannot maintain axial and lateral hydrophobic contacts necessary for polymerization unlike deoxy HbS, thus explaining the unsickling phenomenon upon reoxygenation.
- The sickling process is initially reversible with oxygenation of deoxy HbS, but over time may lead to the formation of irreversibly sickle shaped red cells that fail to return to their normal discoid shape with oxygenation because of membrane damage imparted by repeated cycles of sickling and unsickling in the circulation.
16
Q
A key signaling molecule of the vascular endothelium, has vasodilatory, antiinflammatory, and antiplatelet properties
A
Nitric oxide (NO)
17
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
18
Q
The site of adhesion of sickle red cells is purported to be the __________
A
Postcapillary venule
Site sickle red cells appear to interact with white cells adherent to the endothelium rather than engaging the endothelium directly
19
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.
Monocytes are also highly activated in SCD, and they promote increased endothelial activation by increased production of tumor necrosis factor (TNF)-α and interleukin (IL)-1β.
20
Q
A potent vasoconstrictor and upregulation is associated with adverse outcomes in SCD
A
Endothelin-1
21
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
22
Q
The major component of microparticles in SCD
A
Erythrocyte and platelet microparticles (TF-NEGATIVE)
23
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
24
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
25
Inheritance of only 1 HbS allele along with a normal β-globin gene is termed
Sickle cell trait (HbAS)
## Footnote
* The percentage of HbA is always higher (~60%) than HbS (~40%) in sickle cell trait
* Plasma myeloperoxidase and red cell sickling have been reported to increase during exercise with fluid restriction in HbAS subjects.
26
HbAS cells sickle at O2 tension of approximately _______ torr
15 torr
27
The most common manifestations of HbAS/sickle cell trait
Renal abnormalities
28
A rare but serious renal complication of HbAS
Renal medullary carcinoma
29
# TRUE OR FALSE
HbAS patients do not have increased perioperative morbidity or mortality.
TRUE
HbAS patients do not have increased perioperative morbidity or mortality.
## Footnote
HbAS is considered a generally asymptomatic state.
The life span of HbAS individuals is normal.
30
# TRUE OR FALSE
Unless there is coinheritance of α-thalassemia, the anemia of HbSS individuals is usually hypochromic and microcytic with a steady-state Hb level between 50 g/L and 110 g/L.
FALSE
*Unless there is coinheritance of α-thalassemia*, the anemia of HbSS individuals is usually **normochromic** and **normocytic** with a steady-state Hb level between **50 g/L and 110 g/L**.
## Footnote
* The red cell density is increased with a normal mean cell Hb concentration.
* Serum erythropoietin level is decreased relative to the degree of anemia.
31
Lab parameter that is reflective of persistent low-grade inflammation in SCD
Elevated neutrophil and platelet levels
## Footnote
Platelet levels may be low in individuals with splenic enlargement, however, as a consequence of trapping.
32
SCD can be accurately diagnosed with
High-performance liquid chromatography (HPLC) and isoelectric focusing
## Footnote
No HbA is found in patients with HbSS, HbSC, or HbSβ0 diseases.
Novel point-of-care tests:
* Tendency to produce dense red blood cells, of HbS to precipitate, or solubility testing and sickling of red cells using **sodium metabisulfite**
* **HemoTypeSC**: a qualitative lateral flow immunoassay method to detect the presence of HbA, HbS, and HbC with monoclonal antibodies that detect HbA, HbS, and HbC antigens, but are blind to HbF, and so even newborns with elevated HbF and very low levels of HbA or HbS can be diagnosed
33
Correlate with SCD complications and disease severity
High viscosity and high percentage of dense red cells
34
Dense cells, defined as having more than ____g/L of Hb, are more likely to sickle
111 g/L of Hb
35
Blood viscosity is determined by the:
Hematocrit, red blood cell deformability, red cell aggregation, and plasma viscosity
36
A _________________ **hematocrit-to-viscosity ratio** indicates **improved oxygen-carrying capacity,** and it is _in patients with SCD compared to normal individuals
Higher hematocrit-to-viscosity ratio
Lower in patients with SCD
## Footnote
Low hematocrit-to-viscosity ratio is associated with **recurrent leg ulcers.**
**High viscosity and high percentage of dense red cells** correlate with **SCD complications and disease severity**, and suggest a role for measurement of red blood cell rheology in monitoring patients with SCD and their response to therapy.
37
Sickle Cell Crises
* VOC
* Aplastic crisis
* Sequestration crisis
* Hyperhemolytic crisis
38
The clinical hallmark of SCD
Vasoocclusive Crisis
## Footnote
Pain results from vasoocclusion causing **tissue hypoxia and ischemia.**
Vasoocclusion may affect any tissue, but patients typically report pain in the **chest, lower back, and extremities.**
39
Pain becomes severest by day ____
3
40
VOC become more frequent during
Transition from teenage years to young adulthood
41
Most common precipitating factor of VOC
Episodes may be precipitated by insomnia, emotional stress, dehydration, infection, and cold weather
**In most cases no precipitating factor is found.**
42
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
Reticulocyte count less than 1%
Aplastic crisis
43
The most common cause of Aplastic crisis in SCD
Parvovirus B19 infection
## Footnote
Attaches to the **P-antigen** receptor on erythroid progenitor cells
44
In aplastic crisis, patients usually recover within
2 weeks
45
Cause **severe, life-threatening anemia** due to **sudden, massive pooling of red cells**, typically in the **spleen**, and less commonly, the **liver**
Sequestration Crisis
## Footnote
Splenic sequestration has a high rate of **recurrence**, especially in **children**.
* **Minor sequestration**: Hb of more than 70 g/L
* **Major episode**: Hb is less than 70 g/L or the Hb has decreased by 30 g/L from baseline
46
Splenic sequestration is typically seen in
Children younger than 5 years prior to autoinfarction of the spleen
## Footnote
Also can be seen in adolescents or adults with HbSC disease or HbSβ-thalassemia with persisting splenomegaly
47
Treatment for Splenic sequestration
Small, cautious red cell transfusion
## Footnote
Transfusion carries the risk of **hyperviscosity** when the sequestration crisis resolves and the sequestered red cells are returned to the general circulation.
48
# TRUE OR FALSE
Emergency splenectomy during a sequestration crisis is recommended.
FALSE
Emergency splenectomy during a sequestration crisis is not recommended.
49
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.
2 years or older
50
Splenectomy is recommended
* After the first episode of life-threatening splenic sequestration crisis
* Chronic hypersplenism
51
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)
Hyperhemolytic Crisis
## Footnote
Can occur during resolution of a VOC and from an acute or delayed hemolytic transfusion reactions
52
Acute pain is managed with ___________________ or a combination of these medications.
Opioids, nonsteroidal antiinflammatory drugs, acetaminophen
53
Occasionally, **severe, unrelenting pain** may require **red cell transfusion** to decrease HbS below _________.
30%
54
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**
Acute chest syndrome (ACS)
55
A **leading cause of mortality** in patients with SCD
Acute chest syndrome (ACS)
56
# Etiology of ACS varies depending on age:
Pediatric age group:
Adults:
Pediatric age group: **viral and bacterial infections**
Adults: **fat embolization** resulting from marrow necrosis
57
Important pathogens for ACS
Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Parvovirus B19, respiratory syncytial virus, and influenza
58
Pathogenesis of ACS
Increased intrapulmonary sickling, intrapulmonary inflammation with increased microvascular permeability, and alveolar consolidation
59
Independent risk factors for respiratory failure in ACS
* Age older than 20 years
* Platelet count less than 20 × 109/L
* Multilobar lung involvement
* A history of cardiac disease
60
An independent predictor of **neurologic** complications during hospitalization for ACS
Thrombocytopenia
61
Management of ACS
* 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
62
*Exchange transfusion in ACS is ideal*, but **simple transfusions** to a target Hb of ____g/L are most often used for expediency.
100g/L
63
Should be offered to **all** patients with a **history of ACS** because it reduces the incidence by 50% in children and 73% in adults.
Hydroxyurea
64
Patients with SCD should be **screened for PH** by________________ at steady-state.
Echocardiogram
65
Referral to a pulmonary specialist for further evaluation of PH should be done among the following:
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
66
May be a good modality to image microvascular flow and quantitate cardiac iron overload
Cardiac magnetic resonance
67
Risk of stroke is highest in the _____decade of life followed by a second smaller peak **after age 29 years**.
## Footnote
Overt, clinical stroke in SCD is a macrovascular phenomenon with devastating consequences that affects approximately **11% of patients younger than 20 years**
First decade of life
68
# Types of strokes in SCD:
Ischemic stroke :
Hemorrhagic stroke:
**Ischemic stroke :**children and older adults
**Hemorrhagic stroke:**third decade of life
69
Recurrent stroke is most common in the first ____years following the primary event
2 years following the primary event
70
Risk factors for stroke in SCD
**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
71
The best predictor of stroke risk in SCD
**Increased blood flow velocity** in major intracranial arteries on TCD ultrasonography
## Footnote
* Normal: less than 170 cm/s
* Conditional: between 170 and 200 cm/s
* **High: >200 cm/s**; associated with a 10-fold increase in ischemic stroke in children 2–16 years of age
72
Associated with **increased large-vessel stroke risk**
TNF (−308) G/A promoter polymorphism
73
Variant associated with **protection against stroke**
ENPP1 K173Q
74
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**.
Older than 2 years
## Footnote
* Those with high TCD velocities should be offered a c**hronic red cell transfusion program** for primary stroke prevention.
* Repeat TCD screenings should be done **every 3–12 months**
75
# 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.
Exchange transfusion
## Footnote
Despite chronic transfusions, patients may have a recurrent stroke, especially in patients with **HbS greater than 30%.**
76
# TRUE OR FALSE
The role of transfusion in the setting of hemorrhagic stroke in SCD is less clear than for ischemic stroke.
TRUE
The role of transfusion in the setting of hemorrhagic stroke in SCD is less clear than for ischemic stroke.
77
Once a serum creatinine equal to or greater than _____ mg/dL develops, time to death averages ____ years.
1.5 mg/dL
4 years
## Footnote
**End-stage renal disease** requiring dialysis carries a poor prognosis and is associated with a median survival of **4 years**.
78
The most common cause of **acute renal failure in SCD**.
Dehydration
79
# TRUE OR FALSE
Hyposthenuria, or difficulty concentrating urine, is highly prevalent in SCD, may increase the risk of dehydration, and is reversible
FALSE
**Hyposthenuria**, or difficulty concentrating urine, is highly prevalent in SCD, may increase the risk of dehydration, and is **irreversible**
80
Priapism affects at least_____% of male patients with SCD
The mean age of onset is ____ years
35%
15 years
81
Priapism episodes that last **less than 3 hours**
“stuttering priapism”
82
The major contributors to priapism in SCD
Derangements in **NO** metabolism and **adenosine** signaling
83
More than 95% of priapism is the ________type resulting from **ischemia**, is **painful**, and is a **medical emergency**
“low-flow” type
84
Condition associated with priapism wherein transfusion therapy has resulted in neurologic sequelae
ASPEN syndrome (Association of Sickle Cell Disease, Priapism, Exchange Transfusion)
## Footnote
Thought to be secondary to hyperviscosity
Therefore, must be taken not to increase the hematocrit above 30%.
85
In recalcitrant cases, a__________ is performed, but this results in permanent impotence
Shunt
86
Typical serotypes of ____________________are the principal infectious offenders in osteomyelitis
Salmonella, S. aureus, and Gram-negative bacilli
87
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.
Leukocytes in bone and joint aspirates
88
Osteopenia and osteoporosis are prevalent (30–80%) in patients with SCD, with a predilection for the _____________
Lumbar spine
89
**Vasoocclusion** resulting in infarction of articular surfaces of long bone occurs, most commonly in the **femur** followed by the **humerus**
Avascular Necrosis
90
Classic risk factors for AVN
Concurrent deletional α-thalassemia (−α3.7)
History of frequent VOCs
OTHERS:
Male gender, higher Hb concentration, low HbF, and vitamin D deficiency
91
Polymorphisms in ___________________________ genes are associated with AVN.
BMP6, ANNEXIN A2 KLOTHO, IL1B, and S100B
92
The incidence of leg ulcers varies geographically, with the highest rate reported in_____________
Jamaica
93
Leg ulcers occur on the lower extremities, especially on the _______
Malleoli
94
Protective against leg ulcers
Coinheritance of α-thalassemia
95
Polymorphisms associated with leg ulcers
KL (encoding Klotho), TEK (encoding tyrosine kinase endothelial), and several other genes in the transforming growth factor-β and bone morphogenic protein pathways
96
Characterized by a **rapidly enlarging, tender liver** and **hypovolemia** is akin to splenic sequestration but much more **rare**.
It requires prompt treatment with r**ed cell transfusion.**
Acute hepatic sequestration crisis
97
Ophthalmic changes include “salmon-patch” hemorrhages, peripheral retinal lesions termed black sunbursts, and iridescent spots
Nonproliferative changes
98
Ophthalmic changes include pattern of vascular lesions resembling a marine invertebrate that is termed sea fans
Proliferative changes
99
Characterized by fever, headache, orbital swelling, and visual impairment secondary to optic nerve dysfunction
Orbital compression syndrome
## Footnote
Orbital marrow **infarction** is a common cause.
100
Treatment for Central retinal artery occlusion
Urgent exchange transfusion
101
Treatment for Orbital compression syndrome
Glucocorticoids with the addition of antibiotics
102
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
Functional asplenia
103
Repeated splenic infarctions lead to ______
“autosplenectomy”
104
______________ may lead to reversal of functional asplenia.
Chronic transfusion prior to age 7 years
## Footnote
* **Marrow transplantation and hydroxyurea** have resulted in reversal of functional asplenia in some older patients.
* **Splenic sequestration** typically occurs in children **younger than age 5 years.**
105
# Management During Anesthesia and Surgery
Transfusion to keep Hb levels at approximately ________is recommended
100 g/L
106
________________ occurs in 30% to 50% of SCD patients and two-thirds of all deliveries will have infants with ____________________.
Preterm delivery
Birth weights less than the 50th percentile
107
# Management and Prevention of Infection: Oral penicillin prophylaxis
Between 0 and 3 years of age:
Between 3 and 5 years of age:
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
| Pen V
108
Drug of choice for invasive pneumococcal disease
Ceftriaxone
109
2 factors that **ameliorate many complications of SCD**
Inheritance of α-thalassemia trait
High fetal Hb
## Footnote
Inheritance of α-thalassemia trait : less leg ulcers, gallstone complication etc
110
# 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.
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**.
111
# Hemoglobin F–Inducing Therapies: Mechanism
Stress erythropoiesis
Antiinflammatory
Nitric oxide donor
Increased cyclic guanosine monophosphate
Hydroxyurea
112
# Hemoglobin F–Inducing Therapies: Mechanism
DNA methyltransferase-1 inhibition, ie,hypomethylation
Decitabine
5′-Azacitidine
113
# Hemoglobin F–Inducing Therapies: Mechanism
Histone deacetylase inhibition
Butyrate derivatives
Histone deacetylase inhibitors
114
# Hemoglobin F–Inducing Therapies: Mechanism
P38 mitogen-activated protein kinase pathway
Immunomodulatory drugs
115
# Hemoglobin F–Inducing Therapies: Mechanism
Reversal of γ-globin silencing
Pomalidomide
116
# Hemoglobin F–Inducing Therapies: Mechanism
Induction of FOXO3
Metformin
117
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.**
Hydroxyurea
118
Hydroxyurea is recommended in patients with
* 3 or more VOCs
* History of ACS
* 2 years of age or older and have recurrent moderate to severe pain crises
119
Starting dose of HU
**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.
120
Maximum tolerated dose of HU is defined as
Dose that targets an **absolute neutrophil count of 2.0–4.0 × 109/L** and **absolute reticulocyte count of 100–200 × 109/L**
121
Examples of histone deacetylase inhibitors
Butyrate derivatives (arginine butyrate, sodium phenylbutyrate, isobutyramide)
122
DNA methyltransferase inhibitors
5-azacytidine and decitabine
123
# 5-azacytidine or Decitabine
Incorporates only in DNA and is believed to have a better genotoxicity profile
Decitabine
Incorporates **only in DNA** and is believed to have a **better genotoxicity profile**
## Footnote
Orally administered **decitabine in combination with tetrahydrouridine** is effective in increasing HbF percent, HbF-containing red blood cells, and Hb concentration in sickle cell anemia patients, and is a promising combination for future studies.
Effective for SCD who are refractory to hydroxyurea.
124
The major factor in the **switch from β-globin to γ-globin**
KLF-1–BCL11A axis
125
Most common indications for SCT in SCD
Cerebrovascular disease, recurrent ACS, and frequent VOCs despite adequate hydroxyurea therapy
## Footnote
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.
126
Indications for red cell transfusion in SCD
Symptomatic anemia, ACS, stroke, aplastic and sequestration crises, other major organ damage secondary to vasoocclusion, and occurrence of unrelenting priapism
127
The best-established indication for chronic transfusion
* Stroke
* Abnormal TCD velocity if obtained while on hydroxyurea
* To prevent stroke while hydroxyurea is being initiated
128
Inappropriate indications for transfusion
* Chronic steady-state anemia
* Uncomplicated VO
* Minor surgical procedures
* Infection
* AVN
## Footnote
Simple or exchange transfusion of red blood cells can be used.
129
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.
**Reduced iron overload risk**
Exchange transfusion
130
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**
Hyperhemolysis syndrome
131
Treatments for hyperhemolysis
Steroids, intravenous immunoglobulins, and rituximab
132
A better chelator of **cardiac iron** because of its ability to **cross cell membranes**
Deferiprone
133
An oral pharmaceutical l-glutamine powder
Results to an **increase** in the proportion of the **reduced form of nicotinamide adenine dinucleotides** in the red blood cells of patients with SCD, **reducing the oxidative stress**.
Endari
134
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**
Voxelotor (Oxbryta)
135
A **P-selectin monoclonal antibody** that blocks interaction of P-selectins with leukocytes
Crizanlizumab
## Footnote
Benefits of crizanlizumab are not related to intrinsic red blood cell changes or inhibition of hemolysis.
136
Most of the Hb variants are ________________ mutations in the globin genes (α, β, γ, or δ) resulting from **single nucleotide substitutions.**
Missense mutations
137
The precipitation of the **unstable Hb** molecule within the red cell with attachment to the inner layer of the red cell membrane
Heinz body formation
138
# Unstable Hb variants
Red cells containing **membrane-attached Heinz bodies** have **impaired deformability and filterability** leading to their **premature destruction**
Congenital Heinz body hemolytic anemia
139
# Homozygous or heterezygous
Variant Hbs are usually found in the _____________ state
Heterozygous
140
Mutations in certain residues alter the oxygen affinity of the Hb molecule:
Stabilization of the R (relaxed, oxy) : _________ O2 affinity
Stabilization of the T (tense, deoxy): _________ O2 affinity
**Stabilization of the R (relaxed, oxy)** : high O2 affinity variants and **erythrocytosis**
**Stabilization of the T (tense, deoxy)**: low O2 affinity with enhanced unloading of O2 to the tissues with resultant **cyanosis** and **anemia**
141
The second Hb variant described after HbS
Form **crystals** when incubated with hypertonic saline
Have a propensity for **K+ loss**, which is followed by water loss
HbC
## Footnote
The vast majority of HbCC individuals do not require any therapeutic intervention.
142
The second most common form of SCD in the United States, being found in approximately **25% of individuals with SCD**
HbSC disease
143
Fourth abnormal Hb described
Significant microcytosis without anemia
Hemoglobon E disease
## Footnote
Individuals with **homozygous** HbE are **asymptomatic**; do not require any therapy
**HbE-β-thalassemia** is a rather heterogeneous group of disorders varying from a *mild thalassemia intermedia–like phenotype to a severe transfusion-dependent thalassemia major phenotype*
144
Areas where Hgb E is prevalent
Southeast Asia; in some areas (in the border between **Thailand, Laos, and Cambodia**, the so-called **HbE triangle**)
145
Third variant Hb identified
Hemoglobin D disease
146
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**
M Hbs
147
Mutations that stabilize the molecule in the________________ state lead to low oxygen affinity variants, which can clinically manifest as cyanosis or mild anemia
T (tense, deoxy) state
148
Mutations that stabilize the____________ state or destabilize the T state result in high O2 affinity variants. These variants will cause secondary erythrocytosis
R (relaxed, oxy) state
