sickle cell anemia Flashcards
sickle cell disease
- inheritance
- caused
- aa substitution
- A- co-dominant
- caused by a single base pair substitution in the Beta-globin gene
- glutamic acid to valine substitution
variant hemoglobin, meaning the
mutation imparts a biochemical change in
the hemoglobin molecule.
HbS
heterozygous inheritance or sickle trait
Hb AS
homozygous inheritance; severe disease
Hb SS
most benign of the sickle diseases
sickle cell trait
sickle cell trait:
- HbA:HbS ratio is
- trait is for
- risks
- primary clinical impact
- common in
- 60:40
- protects cells from assuming the sickle shape
- no anemia but risk of splenic infarction at high altitude and death with extreme dehydration/hyperthermia
- primary clinical impact is around child-bearing
- common in African-americand and less in hispanic americans
sickle cell disease includes
- Hb SS
- Hb Sc
- sickle thalassemia
disease modifiers for sickle cell disease
- tissue oxygenation status
- pH
- HbF levels
- co-inheritance of other hb gene abnormalities
Heterozygous inheritance of hemoglobin S offers some protection against
malaria
what leads to polymerization of HbS
RBC deoxygenation
HbS polymers have increased or decreased solubility
decreased
what can increase HbS
cellular dehydration
what happens when RBC become sickle
sickle RBC adhere to the vascular endothelium leading to an activation of coagulation and cytokines cascades leading to increased blood viscosity, entraptment of RBC and leading to vaso-occlusion and pain
Hemoglobin S polymers are unstable leading to _________ (both intra- and extra-vascular).
red cell hemolysis
due to the sickle survival shortened life to 10-16 days what happens to the bone marrow?
marrow erythropoiesis cannot fully compensate in severe hemolysis leading to anemia.
sickle disease the Hb is -_______ and the WBC/platelets are _____
sickle disease the Hb is decreased and the WBC/platelets are normal/elevated
MCV in HbSS
normal to low-normal
MCV in sickle thalassemia
low
MCV in HbSC
low
_____ HbS is insoluble in presence of a concentrated phosphate buffer solution and forms a turbid suspension
Deoxygenated
Sickle solubility test is positive in all sickle conditions but is unable to distinguish between the various genotypes (thus used as a screening test)
yep
Hb electrophoresis on cellulose acetate
- HbS
- HbC
- HbS migrates more slowly than nl hb and fetal hb but migrates in smae position as Hb variants, HbD and HbG
- HbC migrates more slowly and in the same position as HbA2 and HbE
citrates Agar (pH)
- S separated from
- C separated from
- D and G
2. A2 and E
HbS by HPLC
has a distinct retention time
sickle cell complications
multi organ disease
** pregnancy- perilous high morbidity and mortality
erythroid aplasia, often due to parvovirus B19 infection
aplastic crisis
pooling of erythrocytes in the
spleen with acute splenomegaly and shock-like state
sequestration crisis
marked red cell hemolysis
hemolytic crisis
acute pain exacerbations
obstruction of microcirculation with painful tissue hypoxia and microinfarction primarily of bones
Acute pain (vasoocclusive) crisis:
chronic sickle cell complications (6)
- chronic hemolytic anemia
- pain syndrome
- skin- leg ulcers
- endocrinopathies- Growth retard
- Bone disease- acute dactylitis
- ocular
often the first symptom of SCD in babies
acute dactylitis
Presents between 6-18 months as HbF levels decrease
Uncommon once hematopoiesis shifts to axial skeleton (≈ age 6)
Most common lung complication in sickle disease and Most frequent cause of death in adults
acute chest syndrome
Acute chest syndrome
- onset
- defined by
- repeat episodes lead to
- Onset insidious or rapid and fulminant evolving out of
a pain crisis - defined by new:
- pulmonary infiltrate
- pleuritic chest pain -
- fever >38.5
- dyspnea, tachypnea, wheezing, cough - repeat episodes lead to pulmonary HTN and right sided heart failure (cor pulmonale)
obliterative vasculopathy, with severe intimal hyperplasia,
fibrosis, and thrombosis
pulmonary HTN
Joint space narrowing, erosion of acetabular plate –>
chronic pain, can require joint replacement
avascular necrosis
Chronic hemolysis predisposes to leg ulcerations.
Very challenging to treat: hyperbaric oxygen, skin grafting
yep
Free Hb is a potent inhibitor of all_____ → EC dysfunction & NO resistance
NO bioactivity
Proliferative retinopathy similar to diabetic eye disease
Vitreous hemorrhage can lead to retinal detachment and blindness
sickle retinopathy
Narrowing or occlusion of medium and large
cerebral arteries
CNS Vasculopathy & Stroke in SCD
A leading cause of death in
children and adults with SCD
stroke
which sickle type has the highest risk in developing stroke
HbSS
Pathogenesis of stroke (2)
- ischemic infarcts
2. hemorrhagic stroke
progressive vasculopathy arising from neo-vascularization to establish collateral flow because of large vessel occlusion (high incidence in Asians; “puff of smoke”)
moyamoya
in adults over age 29; related
to the formation of moyamoya* vessels in the brain
hemorrhagic stroke SCD
in children aged 2 - 9 years with
second peak in adults over 29 years
ischemic infarct SCD
disease modifying therapy for sickle disease
hydroxyurea
hydroxyurea mechanism
increases HbF production
future managment of sickle disease
- bone marrow transplantation
2. L-glutamine to reduce intracellular oxidant stress and thus reducing pain crises
treatment for sickle cell
treat some of the complications such as pain crisis, acute chest syndrome, ischemic stroke risk, intracranial hemorrhage
red cell transfusion in SCD leads to
iron overload
preventive car and health maintenance (3)
- folic acid- chronic anemia
- penicillin
- health maintenance
