1. Thokozeni Lipato, MD Assistant professor General Internal Medicine Sickle Cell Disease
Megan Lemay
10/29/16

2. Objective
Describe current understanding of sickle cell disease pathophysiology. Describe current understanding of the mechanism of pain in sickle cell disease. Give an overview on how current understanding may result in new treatments for sickle cell disease.
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3. Marilyn J. Telen Blood 2016;127:810-819
The sickle red blood cell as source of multiple pathophysiologic pathways
Marilyn J. Telen Blood 2016;127:
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4. Adhesion Interactions
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5. Adherence of Sickle Red Cells to Endothelium (AR) and the Clinical-Severity Score (CSS) Are Positively and Significantly Correlated and Significantly Correlated (τ = ; P<0.001).
Hebbel RP et al. N Engl J Med 1980;302:
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6. Adhesive interactions involving SS RBCs and WBCs
ICAM-4
BCAM/Lu. Laminin binds it. Epinephrine increases this adhesion.
CD44. Binds with E selectins
Very-late-activation-antigen-4 (VLA4/α4β1) binds to VCAM-1.
VCAM-1 whose expression is induced by cytokines and hypoxia.
Marilyn J. Telen Blood 2016;127:
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7. Manwani D , and Frenette P S Hematology 2013;2013:362-369
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8. Adhesion Interactions: Therapy
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9. E-Selectin Inhibitor GMI 1070
L-selectin is constitutively expressed on leukocytes and mediates lymphocyte recruitment Endothelial cells express two selectins P-selectin which is stored in Weibel-Palade bodies E-selectin; expression induced by cytokines: TNF-α or IL-1β.
Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia. PLoS One. 2014 Jul 2;9(7)
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10. Sevuparin Heparin Does not bind with antithrombin
British Journal of Haematology. 23 AUG 2016
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11. Sevuparin
British Journal of Haematology. 23 AUG 2016
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12. Poloxamer 188
British Journal of Haematology. Volume 173, Issue 1, pages , 5 FEB 2016
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13. Inflammation and coagulation
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14. Platelet activation in patients with sickle cell disease
British Journal of Haematology. Volume 100, Issue 4; pages , 25 DEC 2001
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15. Heeney MM et al. A Multinational Trial of Prasugrel for Sickle Cell VOC. N Engl J Med 2016;374:
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16. TF expression in sickle cell mice.
Pichika Chantrathammachart et al. Blood 2012;120:
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17. Thrombin – Anthrombin complex: Coagulation activation
Pichika Chantrathammachart et al. Blood 2012;120:
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18. Pichika Chantrathammachart et al. Blood 2012;120:636-646
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19. Hemolysis
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20. Proposed model of heme-induced stasis.
Heme elicits vaso-occlusion in transgenic sickle mice via endothelial TLR4 signaling.
Heme/TLR4 signaling activates NF-kB and triggers vaso-occlusion through Weibel-Palade body degranulation and adhesion molecule expression.
TAK-242 (resatorvid), a small-molecule inhibitor of Toll-like receptor (TLR) 4 signaling.
Hemopexin; heme scavenger
John D. Belcher et al. Blood 2014;123:
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21. Proposed model of heme-induced stasis.
John D. Belcher et al. Blood 2014;123:
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22. Pain in Sickle Cell Disease
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23. Hypothesis
Neural response to unrelieved pain may in turn contribute to sickle pathophysiology and further amplify pain Unmyelinated C-fiber nociceptors: a sensory afferent function to transmit information about noxious (painful) stimulation to the central nervous system (CNS) BUT Also serve an efferent function that causes vasodilatation and plasma extravasation, a phenomenon termed neurogenic inflammation The transmission and perception of pain is modified via neuromodulators released from nonneuronal cells, such as mast cells, and contributes to the generation of hyperalgesia.
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24. Cheryl A. Hillery et al. Blood 2011;118:3376-3383
Male HbSS mice exhibit marked hypersensitivity to mechanical, heat, and cold stimuli compared with control HbAA mice.
Cheryl A. Hillery et al. Blood 2011;118:
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25. Cheryl A. Hillery et al. Blood 2011;118:3376-3383
Mechanical force evokes more action potentials in HbSS mice than in HbAA control mice.
Cheryl A. Hillery et al. Blood 2011;118:
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26. Cheryl A. Hillery et al. Blood 2011;118:3376-3383
Cutaneous mechanical hypersensitivity results from enhanced TRPV1 function
Capsaicin receptor Transient Receptor Potential Vanilloid 1 (TRPV1)channel is expressed on many C-fiber nociceptors and is the chief mediator of inflammatory heat pain.
TRPV1 antagonist A
TRPA1 antagonist HC
Cheryl A. Hillery et al. Blood 2011;118:
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27. Cheryl A. Hillery et al. Blood 2011;118:3376-3383
TRPV1 antagonist reversibly improves mechanical hypersensitivity in HbSS mice.
Cheryl A. Hillery et al. Blood 2011;118:
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28. protease activated receptor 2 (PAR2)
neuropeptides substance P (SP)
calcitonin gene-related peptide (CGRP) 
Blood. 2013 Sep 12;122(11)
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29. Haematologica. 2016 May; 101(5): 566–577
Non-selective cannabinoid receptor agonist decreases hyperalgesia in sickle mice
Haematologica May; 101(5): 566–577
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