Hemaglobinopathies Flashcards
What comprises 70% of the RBC?
hemoglobin
Where are the beta globin genes located?
short arm of chromosome 11
What genes are located within the “beta globin gene cluster”?
genes for beta, delta, gamma-A, gamma-G and epsilon globin
What controls expression of the “Beta Globin Gene Cluster”?
A single locus control region
T/F: All globin genes on chromosome 11 are continuously expressed.
F: genes are differently expressed throughout development
What results from rearrangement, deletion or changes to the genes within the Beta Globin Gene Cluster?
gene expression during improper stages of development
What genes are within the Alpha Globin Gene Cluster?
Zeta 1 and 2
Alpha 1 and 2
What does gamma gene expression yield?
Hgb F
What does expression of the delta gene yield?
Hgb A2
What does expression of the beta gene yield?
Hgb A
What are the components of the tetrameric hgb protein?
Products of B1, B2 genes
Products of any 2 of the 4 alpha genes
What are the 4 functions of hgb?
- O transport
- CO2 transport
- pH regulation
- NO sump
NO is inhibited by (3):
hypoxia
activated WBCs
Sickled RBCs
What activates sickled RBCs?
hypoxia
What is ultimately activated by hypoxia (via a few different pathways)?
VCAM-1
What is inactivated by NO (either directly or indirectly)?
VCAM-1
In the presence of Heinz bodies, what will be impaired?
Vasodilation, due to removal of NO
Explain how beta-like globin gene switching progresses during development.
- Initially, epsilon is expressed.
- As epsilon expression decreases, gamma (A +G) are expressed.
- Just before birth, gamma expression declines and beta expression increases.
(4. Delta is expressed a little bit, starting around birth)
What happens to unstable hgb (such as Heinz bodies) within the RBC?
it precipitates
Sickle cell is commonly seen in people of what descent?
African
Mediterranean
What are two types of Sickle Cell variants (non-carriers)?
Sickle Cell Anemia
- Hb SS - Hb SB<sub>0 </sub>Thalassemia
Hb SB+ Thalassemia
Sickle Hb SC (mildest)
T/F: Hb SC has partially normal hgb
F: no normal hgb
What percent of AA are Hgb-AS heterozygous?
8%
If a patient has more symptomatic sickle cell, he/she is higher risk for:
early death
What is the cardinal feature of sickle cell disease?
unpredictable pain
What sickle cell symptom often signals life-threatening complications? What are these?
Acute pain (“precedes 22% of SCD deaths”)
Chest syndrome, stroke, sepsis, organ failure
What is the specific substitution occurs in the beta-S protein?
Val substituted for Glu (at 6)
What abnormality is present in the beta-C protein?
Lys is substituted for Glu (6)
What does the abnormal shape of sickled RBCs cause?
- sluggish blood flow and occlusion
- reperfusion injuries (underperfused tissues are exposed to inflammatory cytokines)
- Endothelial and tissue damage due to oxygen radicals
What structural change causes decreased solubility in Hgb S?
single amino acid substitution at 6th position of beta chain
What factors affect the solubility of Hgb S?
Oxygenation
pH
Temperature (more crises in winter)
How does polymerization occur in Hgb S?
- intermolecular binding of contiguous hydrophobic (valine) molecules occurs when hgb is deoxy
- hydrophobic regions on neighboring chains bind (this is strengthened by electrostatic forces)
- Fibers grow, forming stacks and helical filaments
T/F: Hgb S polymerization is reversible.
T: Most hgb reverts (however, 5-7% will be permanent)
Should you give a patient in SC crisis oxygen?
No–it suppresses EPO production
T/F: Hgb will polymerize if oxygenated.
F: deoxygenated
What is the most important factor in the soluble (non-polymerized) phase of Hgb S?
intracellular concentration of Hgb S
(really didn’t understand the context of this–edit if you knew what big-picture point she was making)
What can block polymerization of Hgb S? How?
Hgb F; copolymerizes with hgb S in an orientation trans to the subunit containing val/hydrophobic region
What protein improves severity of SCD in direct proportion to its concentration (when conc >10%)?
Hgb F
How does hydroxyurea treat SCD?
increases Hgb F production, which decreases SCD crises by 40%
What cell structures are affected by hydroxyurea?
RBC adhesion molecules (decreases them)
4 main ways sickled RBC are different from normal RBC:
- rigid
- dehydrated
- adhere abnormally to vascular endothelium and macrophages
- increase whole-body viscosity
In SCD, hemolysis may be located:
intravascular
Extravascular
What are common SCD crisis triggers?
- hypoxemia
- infection
- climate change (cold)
- stress
- dehydration
- hyperviscosity
- acidosis
Possible Contributory Factors in SCD Vaso-Occlusion:
- Hb S polymer
- Sickle cell deformability
- Sickle blood viscosity
- Fraction of dense sickle cells
- Sickle cell-endothelial cell adherence
- Endothelial cell activation
- Hemostatic activation
- Platelets
- White blood cells
- Vascular tone/architecure
What are 3 major manifestations of SCD?
- vasc occlusion
- infection
- anemia
- inflammation
What are common symptoms of SCD seen in very young children?
dactylitis (due to vasc occlusion)
acute sequestration crisis
What conditions often occur secondary to anemia in SCD?
priapism
leg ulcers
pulmonary hypertension
(due to hemolysis and NO scavenging)
What conditions often occur secondary to vaso-occlusion in SCD?
acute/chronic organ failure
retinopathy
chest syndrome
“painful events”
(due to tissue ischemia, infarction)
What conditions often occur secondary to infection in SCD?
pneumonia
chest syndrome
bacteremia
sepsis
Why is infection common in SCD?
asplenia, making the patient susceptible to encapsulated bacteria and viruses (+ fever)
What are some acute pain syndromes related to SCD?
chest syndrome
cholecystitis
hand-foot syndrome (dactylitis)
pain crises
priapism
splenic infarction
bone infarction
What are some chronic pain syndromes related to SCD?
- arthritis
- avasc necrosis
- leg ulcers
- vertebral body collapse
- osteopenia
- vit D deficiency
- boen infarction
How long do blood cells live in SCD?
14 days–then they release their contents into blood stream
(*this short lifespan means new RBC must be produced at a faster rate)
What scavenges NO in the blood?
free Hgb
What 3 lab values would be abnormal in anemia of SCD?
LDH (elevated)
Bilirubin (elevated)
Reticulocytes (elevated)
What factors contribute to avascular necrosis in SCD?
older age
mild anemia (alpha deletion, Hgb SC, S-Thal)
How renal problems progress in SCD?
- Proteinuria occurs (RBC fragments?)
- Tubular endothelium becomes congested
- Growth factors are induced, which results in fibroblast prolif and matrix synth
- Renal fibrosis results in renal failure
What are common ocular problems in SCD -“ Hgb C”?
hemorrhage
retinitis proliferans
neovascularization
retinopathy (periph)
damage to retinal vasculature
(this was badly worded slide; if you know what she was getting at, fix–or delete)
T/F: High Hgb F is the best way to prevent SCD-associated leg ulcers.
F: “Negative correlation with Hb level and Hb F value”
Leg ulcers are most common in (men/women/children) and in (SA, SS, SC).
Men
SS
What are common fetal complications when the mother has SCD?
- placenta infarctions
- fetal demise
How do you treat pain associated with SCD?
opiates
How do you treat anemia associated with SCD?
blood transfusion
How do you treat severe vasc occlusion associated with SCD?
blood exchange
How does ICAGEN improve anemia in SCD?
blocks RBC ATPase
