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Flashcards in Sickle Cell Disease Deck (15):
1

Hb changes in SCD

-Mutation in B chain leading to Glu-> Val substitution at 6 AA position (HbS) or Glu-> Lys (HbC)
-HbS polymerization is promoted by low O2 tension, low pH, dehydration, increased temperature (latter two based on their affects on the O2 curve- shift to the right)
-HbS polymerization is inhibited by HbF

2

RBC sickling

-Due to polymerization of HbS: in deoxy form the hydrophobic Val are exposed and will aggregate w/ Phe residues of nearby Hb chains causing polymerization of the chains and membrane rigidity (polymers bind to band 3 on membrane)
-This causes membrane damage due to fragmentation and generation of ROS
-Membrane damage leads to exposure of cryptic protein sequences which adhere to vascular endothelium
-Phosphatidyl serine is misplaced to outer membrane and causes pro-thrombotic effect

3

Loss of ion balance in sickled cells

-Losing membrane means losing Na/K pumps (cell cannot regenerate lost proteins)
-Leads to loss of K from cell (and thus loss of H20-> dehydration)
-Sickled cells are not deformable and unable to pass through narrowed vessels
-They are in part responsible for increasing blood viscosity and decreasing blood flow
-SCD patients have 2x the venous viscosity (@ high Hct), thus having anemia (low Hct) partially protects the vasculature

4

Vascular occlusion

-Causes the main clinical symptoms
-Less dense RBCs adhere to venous endothelium, producing partial obstruction to flow
-Dense cells lodge behind the partial obstruction and occlude the vessel
-Hypoxia induced sickling and obstruction spreads retrograde
-This chronic process leads to ischemia, infarction and necrosis
-Manifests as pain, organ damage/failure

5

Hemolysis

-Associated w/ pulmonary hypertension (due to expression of endothelin1 and lack of NO), stroke, leg ulcers, priapism (constitutively erect penis)
-Endothelin1 (ET1) is a potent vasoconstrictor of pulmonary capillary beds, and levels are increased in hypoxia (which occurs due to hemolysis)
-ET1 levels always elevated in SCD, rise sharply before acute inflammatory conditions (acute chest syndrome)
-Increased ET1 and decreased NO together result in vasoconstriction, increasing capillary transit time, endothelial expression of VCAM1 (adhesion protein)
-This increases RBC adherence and enhancing microvascular obstruction

6

Nitric Oxide (NO) 1

-Potent vasodilator generated from Arginine, can be inactivated by free Hb in blood stream (reduced by Hb to NO3-) or arginase
-NO reduces adhesive actions of blood cells and endothelium and decreases expression of VCAM on endothelium
-NO is used for pulmonary vasodilation via inhalation (systemic use not effective due to inactivation by Hb->metHb)
-NO can produce ROS

7

Nitric Oxide (NO) 2

-Arginine levels are low in SCD patients, and drop during acute chest syndrome (ACS)
-NO3- increased in ACS, suggesting depletion of NO
-Lysed RBCs liberate Arginase which destroys arginine and renders endothelium unable to produce more NO
-Reduced NO levels means it cannot prevent platelet activation and aggregation, and also cannot prevent expression of VCAM/ICAM, P/E-selectin on endothelial surfaces
-Taken together this means that low NO leads to vasoconstriction and easily clotable blood, exacerbating the already static flow

8

Common types of SCD

-Sickle cell anemia (homozygous HbS, AKA HbSS)
-Sickle-C disease (double heterzoygote)
-S B+ thalassemia (double heterozygote)
-S Bo thalassemia (double heterozygote)

9

Manifestations of sickling

-Chronic hemolytic anemia
-Intermittent acute events (crises)
-Increased susceptibility to bacterial infection (due to asplenia or abnormal complement activation)
-Specific organ syndromes due to infarction/necrosis

10

Acute pain episodes

-Most often due to marrow ischemia (poorly localized)
-Only a minority of patients are severely affected and required hospitalization (skewed distribution w/ each genotype)
-Associated w/ decreased survival
-Management is relief w/ proper analgesics

11

Acute chest syndrome

-Acute pulmonary infiltrate w/ cough and fever, difficult to distinguish infarction from infection
-A major cause of morbidity and mortality in SCD
-Can be due to infection (usually mycoplasma, chlamydia, viral), or infarction
-Worsening hypoxia causes vicious cycle of increasing Hb polymerization, sickling, and thus increasing lung infarction and pain
-Can lead to adult respiratory distress syndrome (ARDS) and fibrosis

12

Fat embolism syndrome

-BM necrosis can release marrow elements into the circulation causing acute inflammation rxn against the marrow fat
-This leads to onset of fever, tachypnea, severe hypoxia and altered mental status

13

Organ damage syndromes 1

-Proliferative sickle retinopathy: earlier onset in sickle-C disease. Progresses through 5 stages and results in retinal detachment and blindness
-Auto-splenectomy: due to ischemic necrosis, leads to susceptibility of infection from encapsulate organisms
-Cholelithiasis (bili stones): due to increased bili levels from hemolysis
-Avascular necrosis of bone (osteonecrosis): Vasoocclusion of BM sinuses leads to ischemia/necrosis. Necrosed BM is easily infected leading to ostomyelitis

14

Organ damage syndromes 2

-Renal manifestations: glomerular hypertrophy, increased renal blood flow and GFR, papillary necrosis, hyposthenuria (can't conserve H2O), renal insufficiency, loss of EPO
-HbSS mean survival is mid-40s, HbSC is late 60s. Stroke is leading cause of death in children, renal failure and chronic organ damage is leading cause of death in adults

15

Rx of SCD

-Supportive care: hydration, pain management, infection Rx, organ complications
-Transfusions for acute (anemia and hypoxia) and chronic (suppress Hb S and stroke prevention) complications (don't forget risks- Fe overload, transfusion reactions, allo-immunizations, viral transmission)
-Hydroxyurea increases HbF production, in turn decreasing HbS polymerization, obstruction, and membrane damage/hemolysis
-Hydroxyurea used only to alleviate crises
-Other agents to increase HbF expression: 5-azadeoxycytidine, butyrate
-BM transplantation and gene therapy