pathophysiology of vaso -occlusion , an update · basicpathophysiology of vaso-occlusion. sickle...
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Pathophysiology of Pathophysiology of VasoVaso--OcclusionOcclusion, , anan
UpdateUpdate
Fisiopatologia da VasoFisiopatologia da Vaso--OclusãoOclusão--AtualizaAtualizaçção ão
Nicola Conran
Hemocentro/FCM/UNICAMP
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Steinberg; Trends Pharm Sci (2006)
Sickle Cell Disease Vaso-occlusion
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1) HbS Polymer Formation: RBC deoxygenation
High intracellular [HbS]
Low [HbF]
Low pH
2) Chronic Inflammatory State
3) Increased RBC Transit Time in the Microcirculation:
Cell-Endothelium adhesion
Cell-cell aggregate formation
Abnormal cationic homeostasis
Abnormal vasoregulation
4) Other factors: Oxidative/nitrostative stress
Thrombin formation
Basic Pathophysiology of Vaso-occlusion
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Sickle Cell Disease and the Chronic Inflammatory State
Endothelial adhesive
interactions
Endothelial damage by
sickled red cells
Ischemia-Reperfusion Injury
Cellular activation and up-regulation of
endothelial adhesion molecules
E-selectin, VCAM-1, ICAM-1
Further adhesion of red cells and
leukocytes to endothelium
Elevation of circulating levels of
cytokines and chemokines
IL-1, TNFα, GM-CSF, IL-8
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Red Blood Cells and Vaso-occlusion
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Endothelial Cell SS RBC
BCAM/LU
Laminin
Trombospondin
Fibronectin
VCAM-1 VLA-4
CD36
Red Blood Cells and Vaso-occlusion
Adapted from Setty et al (2000) Blood
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• Augmented leukocyte numbers are associated
with increased morbidity and mortality in SCD
• Increased leukocyte numbers are associated
with an elevated risk for CVA and acute chest
syndrome in young patients
Leukocytes and Vaso-occlusion
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ICAM-1
Mac-1
Chemotaxis
Endothelial Cell
neutrophil
Autologous
IgG
ICAM-4
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Frenette & Atweh (2007) J Clin Invest 117: 850
Leukocytes and Vaso-occlusion
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Cremaster muscle preparation in SS mouse
After TNFαααα stimulation
Frenette et al (2004) Microcirculation; 11:169
http://www.mssm.edu/labs/frenette/microcirc.shtml
Leukocyte
Vascular
Wall
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• Eosinophils: Elevated numbers
Increased adhesive properties (FN)
• Therapy with hydroxyurea (HU):
The benefits of HU are often observed before an
increase in HbF production; due to reduction in neutrophil
numbers?
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Platelets and Vaso-occlusion
• Platelets circulate in an activated state in SCD
• Increased liberation of β-tromboglobulina, PF-4, TSP, IL-1
• P-selectina, GPIIb/IIIa increased
• Adhesive properties increased
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Nitric Oxide (NO) and Vaso-occlusion
• NO: signaling gas
produced mainly by endothelial cells
half-life of seconds
• cGMP: Principal NO second messenger
• NO: Essential for vascular hemostasis
anti-thromotic
anti-adhesive
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SCD and Reduced NO Bioavailability
• L-arginine levels
• consumption by ROS
• Scavenging by cell-free hemoglobin – intravascular hemolysis
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Scavenging of NO by cell-free hemoglobin
Reduced NO Bioavailability
Reiter et al., Nature Medicine, vol 8, 2002
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Manifestations of reduced NO bioavailability in SCD
• Pulmonary Hypertension
• Priapism
• Leg Ulcer
• CVA
• Renal insufficiency
• Gastrointestinal Pain
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Role of Role of cAMPcAMP in in alteredaltered leukocyteleukocyte functionfunction in SCDin SCD
cAMP
• Cyclic nucleotide
• Intracellular signaling molecule
• Mediates signaling of hormones, neurotransmitters and cytokines
• Intracellular targets: protein kinase A (PKA), ionic channels, Epac
• Long and short term responses
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Leukocyosis
Vascular Vascular
InflammationInflammation
Prostaglandin
(E1/E2)GM-CSF IL-8
Production de cytokines
IL-6
Intracellular cAMP
Conran et al., (2007) Annals Hematol
Conran et al., (2007) Br J Haematol
Role of Role of cAMPcAMP in in alteredaltered leukocyteleukocyte functionfunction in SCDin SCD
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Inhibition of cell death chemotaxis
Exacerbation of
inflammation state
Cellular adhesion
Intracellular cAMP
Vaso-occlusion
Canalli et al., (2007) Eu J Haematol
Conran et al., (2007) Br J Haematol
Role of Role of cAMPcAMP in in alteredaltered leukocyteleukocyte functionfunction in SCDin SCD
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Cokic et al., Blood, 2006
Effects of Hydroxyurea in the Microcirculation
NO
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Adapted from Mack & Kato Int J Biochem Cell Biol,
2006
Therapeutic targets for the prevention and treatment of
vaso-occlusion in SCD
NO donors
Anti-adhesive therapies,
eg. Small molecule cyclic ααααvββββ3
antagonists
PKA inhibition?
Leukocyte
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SCD Vaso-occlusion
↓ NO Bioavailability
Inflammation
Cell Adhesion
Vasoconstriction
Propagation of the fibrin plaque
Obstruction of rigid RBC
Diminished Blood Flow
Vas-occlusionSwitzer et al., Lancet
Neurol 2006; 5:501
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Acknowledgments
Prof. Dr. Fernando F. Costa
Andreia Canalli
Carla Franco-Penteado
Carolina Lanaro
Sheley Gambero