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
