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

Slides:

Advertisements

Similar presentations

Acute and Chronic Inflammation. W.B. Saunders Company items and derived items Copyright (c) 1999 by W.B. Saunders Company.

Advertisements

G. S / AIH 2006 Graft-versus-Host disease Physiopathology Gérard Socié, MD PhD Hospital Saint Louis Translating experimental into clinical knowledge.

Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease by Marilyn J. Telen Blood Volume 127(7): February 18, 2016 ©2016 by.

Date of download: 6/23/2016 From: Glucocorticoid Therapy for Immune-Mediated Diseases: Basic and Clinical Correlates Ann Intern Med. 1993;119(12):

Mechanism of Action of Colchicine in the Treatment of Gout

Inflammation (1 of 5) Ali Al Khader, M.D. Faculty of Medicine

W5D3H3: Sensory Receptors

Pathophysiology of irritable bowel syndrome

Roles of Mas-related G protein–coupled receptor X2 on mast cell–mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases

Figure 2 Cell-mediated disease mechanisms of lupus nephritis

Mast cell activation contributes to sickle cell pathobiology and pain in mice by Lucile Vincent, Derek Vang, Julia Nguyen, Mihir Gupta, Kathryn Luk, Marna.

by Dachuan Zhang, Chunliang Xu, Deepa Manwani, and Paul S. Frenette

GLEE-ful for sickle cell pain?

Neurovascular Aspects of Skin Neurogenic Inflammation

Chemical Mediators Dr Shoaib Raza.

by William C. Aird Blood Volume 101(10): May 15, 2003

The Hematologic System as a Marker of Organ Dysfunction in Sepsis

Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea by Camila Bononi Almeida, Lucas.

Road signs guiding leukocytes along the inflammation superhighway

Serum Levels of Substance P Are Elevated in Patients With Sickle Cell Disease and Increase Further During Vaso-Occlusive Crisis by Lisa A. Michaels, Kwaku.

Nat. Rev. Nephrol. doi: /nrneph

Leukocyte-endothelial cell interactions: Molecular mechanisms and implications in gastrointestinal disease Julián panés*, D.Neil Granger‡ Gastroenterology

Neuropeptide Control Mechanisms in Cutaneous Biology: Physiological and Clinical Significance Eva M.J. Peters, Marna E. Ericson, Junichi Hosoi, Kristina.

Nat. Rev. Nephrol. doi: /nrneph

Neurophysiological, Neuroimmunological, and Neuroendocrine Basis of Pruritus Martin Steinhoff, John Bienenstock, Martin Schmelz, Marcus Maurer, Ed Wei,

Microvascular responses to sepsis: clinical significance

Toll-like receptors in Borrelia burgdorferi-induced inflammation

Chapter 14 Immune Response in Space and Time

Role of COX-2 Inhibitors in the Evolution of Acute Pain Management

HU for acute treatment of sickle VOC?

Therapeutic pipeline for atopic dermatitis: End of the drought?

Figure 1 The coagulation system

Neural Regulation of Endothelial Cell-Mediated Inflammation

Activated monocytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion by John D. Belcher, Paul H. Marker,

Nat. Rev. Nephrol. doi: /nrneph

From immunosuppression to tolerance

Nat. Rev. Nephrol. doi: /nrneph

Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

Volume 20, Issue 1, Pages (February 2013)

Jo-Ellen Murphy, Caroline Robert, Thomas S. Kupper

H. Zhao, A. Alam, Q. Chen, M. A. Eusman, A. Pal, S. Eguchi, L. Wu, D

Inflammatory health effects of indoor and outdoor particulate matter

Advances in the Treatment of Sickle Cell Disease

R. Clive Landis, PhD, George Asimakopoulos, Mike Poullis, Dorian O

Thrombosis and Inflammatory Bowel Disease

Anti-inflammatory Agents: Present and Future

Mechanisms Underlying Inflammation in Neurodegeneration

A TR(I)P to Pruritus Research: Role of TRPV3 in Inflammation and Itch

The role of the nervous system in rhinitis

Neuroimmunology of Stress: Skin Takes Center Stage

Mechanisms by which HRV increases susceptibility to bacterial infection. Mechanisms by which HRV increases susceptibility to bacterial infection. (1) HRVs.

Mechanisms of eosinophil-associated inflammation

Pathogenesis of allergic rhinitis

Stress, chronic inflammation, and emotional and physical well-being: Concurrent effects and chronic sequelae George P. Chrousos, MD Journal of Allergy.

Cytokines and chemokines orchestrate atopic skin inflammation

Molecular and cellular mechanisms of allergic disease

Schematic representation of the pathophysiology (in part) of sickle cell anemia. A single gene mutation (GAG→GTG and CTC→CAC) results in a defective hemoglobin.

Nat. Rev. Rheumatol. doi: /nrrheum

Systemic effects of local allergic disease

Trousseau's syndrome: multiple definitions and multiple mechanisms

Figure 1. Initiation of vasculitic lesions in small vessels by ANCA-activating cytokine-primed neutrophils in the wrong place and at the wrong time. Figure.

How I treat disseminated intravascular coagulation

A binding relationship with thrombin

Interaction of platelet-decorated VWF strings with leukocytes and infected red blood cells in vitro. Interaction of platelet-decorated VWF strings with.

Edward M. Boyle, Timothy H. Pohlman, Carol J. Cornejo, Edward D

Myeloproliferative neoplasms and thrombosis

Figure 3 The possible role of keratinocytes in CRPS pathophysiology

Increasingly Irritable and Close to Tears: TRPA1 in Inflammatory Pain

Airway smooth muscle: An immunomodulatory cell

A schematic diagram showing the mechanism by which L5 triggers platelet activation and aggregation. A schematic diagram showing the mechanism by which.

Presentation transcript:

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

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. Footer Date

Marilyn J. Telen Blood 2016;127:810-819 The sickle red blood cell as source of multiple pathophysiologic pathways Marilyn J. Telen Blood 2016;127:810-819 Footer Date

Adhesion Interactions Footer Date

Adherence of Sickle Red Cells to Endothelium (AR) and the Clinical-Severity Score (CSS) Are Positively and Significantly Correlated and Significantly Correlated (τ = +0.666; P<0.001). Hebbel RP et al. N Engl J Med 1980;302:992-995. Footer Date

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;127:810-819 Footer Date

Manwani D , and Frenette P S Hematology 2013;2013:362-369 Footer Date

Adhesion Interactions: Therapy Footer Date

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) Footer Date

Sevuparin Heparin Does not bind with antithrombin British Journal of Haematology. 23 AUG 2016 Footer Date

Sevuparin British Journal of Haematology. 23 AUG 2016 Footer Date

Poloxamer 188 British Journal of Haematology. Volume 173, Issue 1, pages 145-149, 5 FEB 2016 Footer Date

Inflammation and coagulation Footer Date

Platelet activation in patients with sickle cell disease British Journal of Haematology. Volume 100, Issue 4; pages 741-749, 25 DEC 2001 Footer Date

Heeney MM et al. A Multinational Trial of Prasugrel for Sickle Cell VOC. N Engl J Med 2016;374:625-635 Footer Date

TF expression in sickle cell mice. Pichika Chantrathammachart et al. Blood 2012;120:636-646 Footer Date

Thrombin – Anthrombin complex: Coagulation activation Pichika Chantrathammachart et al. Blood 2012;120:636-646 Footer Date

Pichika Chantrathammachart et al. Blood 2012;120:636-646 Footer Date

Hemolysis Footer Date

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;123:377-390 Footer Date

Proposed model of heme-induced stasis. John D. Belcher et al. Blood 2014;123:377-390 Footer Date

Pain in Sickle Cell Disease Footer Date

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. Footer Date

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;118:3376-3383 Footer Date

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;118:3376-3383 Footer Date

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-425619 TRPA1 antagonist HC-030031 Cheryl A. Hillery et al. Blood 2011;118:3376-3383 Footer Date

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;118:3376-3383 Footer Date

protease activated receptor 2 (PAR2) neuropeptides substance P (SP) calcitonin gene-related peptide (CGRP) Blood. 2013 Sep 12;122(11) Footer Date

Haematologica. 2016 May; 101(5): 566–577 Non-selective cannabinoid receptor agonist decreases hyperalgesia in sickle mice Haematologica. 2016 May; 101(5): 566–577 Footer Date