Pathophysiology and Pharmacology of Sickle Cell Disease Flashcards
Define SCD
Autosomal recessive genetic blood disorder affecting the hemoglobin beta chain
Multisystem disease associated with episodes of acute illness and prograssive organ damage
Sickle Cell Trait
Only one allele
Asymptomatic
Sickle Cell Disease
Both alleles
Develop anemia
SCD Results in
Impaired circulation, vasocclusive disorder, vessel damage and RBC destruction with severe morbidity and early mortality
Delayed growth and height/weight
Sickling mechanism
Deoxygenation HgbS –> conformation change
Val6 forms a bond with Phe85 and Leu88
Pairing HbS monomers aggregate and polymerize to form long, ridged fibers –> deform the RBC
Increases blood viscosity and adhere to vascular walls
Cells become dense and inflexible
10-20 day life span
Factors promoting sickling
Low oxygen Increased CO2 Increased 2-3 bisphosphoglycerate High HbS: dehydration Low HbF
HbF
Gamma globin chains bind to HbS chain and inhibits polymerization
Mutation in SCD
Glutamic acid –> valine (sickling!)
Vassocclusive Inflammation
Increase granulocytic oxygen burst –> ROS –> damage
Up regulation pro-inflammatory cytokines
Activate PMNs adn Monocytes –> more cytokines
PMNs cause endothelium adhesion
Vasocclusion Endothelial Cell Activation
Increase expression of adhesion molecules for leukocytes
Increased cytokines and chemotatic factors
Vasocclusive Multiple Prothrombotic Effects
Von-Willibrand Factor – depletes anticoagulatns and increase plasminogen activator inhibitor and platelet activating factory leading to aggregation and degranulation
Vasocclusive Presentation
Hand and Foot Syndrome: pain and swelling
Joints and extremeties: pain
Abdomen and hepatic pain
Splenic Sequestration
Spleen removes old RBC and holds reserve of blood
Increased amount of monocytes
VO – SS – splenomegaly and decreased blood volume – hypotension
Risk of sepsis
Aplastic
Destruction of erythroid precursors in marrow
Low reticulocyte count
Viral infection – get shots!
Complications!
Neurological
Priapism
Leg Ulcers
Acute chest syndrome
Acute chest syndrom
Sickled red cells occlude the pulmonary vasculature
Chronic Complications
Cholelithiasis CV Bone adn joint destruction Ocular Renal
Preventative therapy does what?
Fetal Hgb inducer
Hydroxyurea
Induces proliferation of early erythroid progenitors and increase NO
Antioxidant properties
Alternative to chronic transfusion
Increases MCV
Sodium butyrate
Inhibit histone deacetylation –> no DNA transcription
Decitabine
Inhibit DNA methylation (prevents switch from gamma to beta
Allogenic stem cell transplantation
Curative >16 Most don't have donors Can induce malignancy Risk of Graft VS Host Disease (autoimmune)
Other treatment options
Inhaled cromolyn sodium
Omega 3 FA
Gene therapy: transfer anti-sickling gene
