50 Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities Flashcards
The iron-containing oxygen-transport metalloprotein found in abundance in the red blood cells.
Hemoglobin (Hb)
Accounts for about 2% of the Hb of normal adults
Minor adult Hb (HbA2 [α2δ2])
The prosthetic group of Hb
Heme (ferroprotoporphyrin IX)
The heme group is located in a crevice between the E and F helices in each globin chain
The non–α (β, γ, δ, or ε)-globin chains are all _____amino acids in length.
146 amino acids
P50 is standardized at ___°C and pH ____°C.
37°C
pH 7.20
The point at which the Hb is one-half saturated with oxygen and is the usual measurement of oxygen affinity
P50
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.
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
The most common SCD genotype is
in the US
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
HbE prevalence is second only to HbS, and found principally in Burma, Thailand, Laos, Cambodia, Malaysia, and Indonesia, but not in ______
Asia
China
As with HbS and HbC, HbE appears to confer some resistance to infection with malaria.
Single nucleotide mutations in:
HbS:
HbD:
HbC:
HbE:
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)
The World Health Organization estimates that ____% of the world population carries a gene for a hemoglobinopathy.
5%
The sine qua non of sickle cell anemia is
Glu→Val substitution in the sixth amino acid of the β-globin molecule
Aggregation of deoxy HbS molecules into polymers occurs when aggregates reach a thermodynamically critical size
Homogenous nucleation
The smallest aggregate formed that favors polymer growth
Critical nucleus
Addition of subsequent deoxy HbS molecules to already formed polymers
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.
A key signaling molecule of the vascular endothelium, has vasodilatory, antiinflammatory, and antiplatelet properties
Nitric oxide (NO)
Released as a consequence of sickle red cell hemolysis converts arginine to ornithine, thereby limiting l-arginine availability for NO synthesis.
L-arginase
The site of adhesion of sickle red cells is purported to be the __________
Postcapillary venule
Site sickle red cells appear to interact with white cells adherent to the endothelium rather than engaging the endothelium directly
TRUE OR FALSE
Neutropenia is an adverse prognostic factor in sickle cell anemia.
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.
A potent vasoconstrictor and upregulation is associated with adverse outcomes in SCD
Endothelin-1
Characteristics of the vascular beds in sickle cell anemia
Large vessel intimal hyperplasia and smooth muscle proliferation
Lipid-laden plaques of atherosclerotic vascular disease are not present
The major component of microparticles in SCD
Erythrocyte and platelet microparticles (TF-NEGATIVE)
The major contributor of microparticle-dependent coagulation activation in SCD
Activation of the intrinsic pathway of coagulation by TF-negative, red cell, and platelet microparticles through a phosphatidylserine-dependent mechanism
Adenosine Signaling
Adenosine A2A receptor:
Adenosine A2B receptor:
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
Inheritance of only 1 HbS allele along with a normal β-globin gene is termed
Sickle cell trait (HbAS)
- 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.
HbAS cells sickle at O2 tension of approximately _______ torr
15 torr
The most common manifestations of HbAS/sickle cell trait
Renal abnormalities
A rare but serious renal complication of HbAS
Renal medullary carcinoma
TRUE OR FALSE
HbAS patients do not have increased perioperative morbidity or mortality.
TRUE
HbAS patients do not have increased perioperative morbidity or mortality.
HbAS is considered a generally asymptomatic state.
The life span of HbAS individuals is normal.
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.
- The red cell density is increased with a normal mean cell Hb concentration.
- Serum erythropoietin level is decreased relative to the degree of anemia.
Lab parameter that is reflective of persistent low-grade inflammation in SCD
Elevated neutrophil and platelet levels
Platelet levels may be low in individuals with splenic enlargement, however, as a consequence of trapping.
SCD can be accurately diagnosed with
High-performance liquid chromatography (HPLC) and isoelectric focusing
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
Correlate with SCD complications and disease severity
High viscosity and high percentage of dense red cells
Dense cells, defined as having more than ____g/L of Hb, are more likely to sickle
111 g/L of Hb
Blood viscosity is determined by the:
Hematocrit, red blood cell deformability, red cell aggregation, and plasma viscosity
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
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.
Sickle Cell Crises
- VOC
- Aplastic crisis
- Sequestration crisis
- Hyperhemolytic crisis
The clinical hallmark of SCD
Vasoocclusive Crisis
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.
Pain becomes severest by day ____
3
VOC become more frequent during
Transition from teenage years to young adulthood
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.
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
The most common cause of Aplastic crisis in SCD
Parvovirus B19 infection
Attaches to the P-antigen receptor on erythroid progenitor cells
In aplastic crisis, patients usually recover within
2 weeks
Cause severe, life-threatening anemia due to sudden, massive pooling of red cells, typically in the spleen, and less commonly, the liver
Sequestration Crisis
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
Splenic sequestration is typically seen in
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
Treatment for Splenic sequestration
Small, cautious red cell transfusion
Transfusion carries the risk of hyperviscosity when the sequestration crisis resolves and the sequestered red cells are returned to the general circulation.
TRUE OR FALSE
Emergency splenectomy during a sequestration crisis is recommended.
FALSE
Emergency splenectomy during a sequestration crisis is not recommended.
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
Splenectomy is recommended
- After the first episode of life-threatening splenic sequestration crisis
- Chronic hypersplenism
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
Can occur during resolution of a VOC and from an acute or delayed hemolytic transfusion reactions
Acute pain is managed with ___________________ or a combination of these medications.
Opioids, nonsteroidal antiinflammatory drugs, acetaminophen
Occasionally, severe, unrelenting pain may require red cell transfusion to decrease HbS below _________.
30%
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)
A leading cause of mortality in patients with SCD
Acute chest syndrome (ACS)
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
Important pathogens for ACS
Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Parvovirus B19, respiratory syncytial virus, and influenza
Pathogenesis of ACS
Increased intrapulmonary sickling, intrapulmonary inflammation with increased microvascular permeability, and alveolar consolidation
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
An independent predictor of neurologic complications during hospitalization for ACS
Thrombocytopenia
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
Exchange transfusion in ACS is ideal, but simple transfusions to a target Hb of ____g/L are most often used for expediency.
100g/L
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
Patients with SCD should be screened for PH by________________ at steady-state.
Echocardiogram
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
May be a good modality to image microvascular flow and quantitate cardiac iron overload
Cardiac magnetic resonance
Risk of stroke is highest in the _____decade of life followed by a second smaller peak after age 29 years.
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
Types of strokes in SCD:
Ischemic stroke :
Hemorrhagic stroke:
Ischemic stroke :children and older adults
Hemorrhagic stroke:third decade of life
Recurrent stroke is most common in the first ____years following the primary event
2 years following the primary event
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
The best predictor of stroke risk in SCD
Increased blood flow velocity in major intracranial arteries on TCD ultrasonography
- 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
Associated with increased large-vessel stroke risk
TNF (−308) G/A promoter polymorphism
Variant associated with protection against stroke
ENPP1 K173Q
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
- 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
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
Despite chronic transfusions, patients may have a recurrent stroke, especially in patients with HbS greater than 30%.
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.
Once a serum creatinine equal to or greater than _____ mg/dL develops, time to death averages ____ years.
1.5 mg/dL
4 years
End-stage renal disease requiring dialysis carries a poor prognosis and is associated with a median survival of 4 years.
The most common cause of acute renal failure in SCD.
Dehydration
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
Priapism affects at least_____% of male patients with SCD
The mean age of onset is ____ years
35%
15 years
Priapism episodes that last less than 3 hours
“stuttering priapism”
The major contributors to priapism in SCD
Derangements in NO metabolism and adenosine signaling
More than 95% of priapism is the ________type resulting from ischemia, is painful, and is a medical emergency
“low-flow” type
Condition associated with priapism wherein transfusion therapy has resulted in neurologic sequelae
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%.
In recalcitrant cases, a__________ is performed, but this results in permanent impotence
Shunt
Typical serotypes of ____________________are the principal infectious offenders in osteomyelitis
Salmonella, S. aureus, and Gram-negative bacilli
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
Osteopenia and osteoporosis are prevalent (30–80%) in patients with SCD, with a predilection for the _____________
Lumbar spine
Vasoocclusion resulting in infarction of articular surfaces of long bone occurs, most commonly in the femur followed by the humerus
Avascular Necrosis
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
Polymorphisms in ___________________________ genes are associated with AVN.
BMP6, ANNEXIN A2 KLOTHO, IL1B, and S100B
The incidence of leg ulcers varies geographically, with the highest rate reported in_____________
Jamaica
Leg ulcers occur on the lower extremities, especially on the _______
Malleoli
Protective against leg ulcers
Coinheritance of α-thalassemia
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
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.
Acute hepatic sequestration crisis
Ophthalmic changes include “salmon-patch” hemorrhages, peripheral retinal lesions termed black sunbursts, and iridescent spots
Nonproliferative changes
Ophthalmic changes include pattern of vascular lesions resembling a marine invertebrate that is termed sea fans
Proliferative changes
Characterized by fever, headache, orbital swelling, and visual impairment secondary to optic nerve dysfunction
Orbital compression syndrome
Orbital marrow infarction is a common cause.
Treatment for Central retinal artery occlusion
Urgent exchange transfusion
Treatment for Orbital compression syndrome
Glucocorticoids with the addition of antibiotics
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
Repeated splenic infarctions lead to ______
“autosplenectomy”
______________ may lead to reversal of functional asplenia.
Chronic transfusion prior to age 7 years
- 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.
Management During Anesthesia and Surgery
Transfusion to keep Hb levels at approximately ________is recommended
100 g/L
________________ 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
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
Drug of choice for invasive pneumococcal disease
Ceftriaxone
2 factors that ameliorate many complications of SCD
Inheritance of α-thalassemia trait
High fetal Hb
Inheritance of α-thalassemia trait : less leg ulcers, gallstone complication etc
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.
Hemoglobin F–Inducing Therapies: Mechanism
Stress erythropoiesis
Antiinflammatory
Nitric oxide donor
Increased cyclic guanosine monophosphate
Hydroxyurea
Hemoglobin F–Inducing Therapies: Mechanism
DNA methyltransferase-1 inhibition, ie,hypomethylation
Decitabine
5′-Azacitidine
Hemoglobin F–Inducing Therapies: Mechanism
Histone deacetylase inhibition
Butyrate derivatives
Histone deacetylase inhibitors
Hemoglobin F–Inducing Therapies: Mechanism
P38 mitogen-activated protein kinase pathway
Immunomodulatory drugs
Hemoglobin F–Inducing Therapies: Mechanism
Reversal of γ-globin silencing
Pomalidomide
Hemoglobin F–Inducing Therapies: Mechanism
Induction of FOXO3
Metformin
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
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
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.
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
Examples of histone deacetylase inhibitors
Butyrate derivatives (arginine butyrate, sodium phenylbutyrate, isobutyramide)
DNA methyltransferase inhibitors
5-azacytidine and decitabine
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
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.
The major factor in the switch from β-globin to γ-globin
KLF-1–BCL11A axis
Most common indications for SCT in SCD
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.
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
The best-established indication for chronic transfusion
- Stroke
- Abnormal TCD velocity if obtained while on hydroxyurea
- To prevent stroke while hydroxyurea is being initiated
Inappropriate indications for transfusion
- Chronic steady-state anemia
- Uncomplicated VO
- Minor surgical procedures
- Infection
- AVN
Simple or exchange transfusion of red blood cells can be used.
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
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
Treatments for hyperhemolysis
Steroids, intravenous immunoglobulins, and rituximab
A better chelator of cardiac iron because of its ability to cross cell membranes
Deferiprone
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
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)
A P-selectin monoclonal antibody that blocks interaction of P-selectins with leukocytes
Crizanlizumab
Benefits of crizanlizumab are not related to intrinsic red blood cell changes or inhibition of hemolysis.
Most of the Hb variants are ________________ mutations in the globin genes (α, β, γ, or δ) resulting from single nucleotide substitutions.
Missense mutations
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
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
Homozygous or heterezygous
Variant Hbs are usually found in the _____________ state
Heterozygous
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
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
The vast majority of HbCC individuals do not require any therapeutic intervention.
The second most common form of SCD in the United States, being found in approximately 25% of individuals with SCD
HbSC disease
Fourth abnormal Hb described
Significant microcytosis without anemia
Hemoglobon E disease
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
Areas where Hgb E is prevalent
Southeast Asia; in some areas (in the border between Thailand, Laos, and Cambodia, the so-called HbE triangle)
Third variant Hb identified
Hemoglobin D disease
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
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
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
